Part IV: Long COVID and Axis Dysregulation

Posted by Carly Webb on

To say that we have been “stressed” is an understatement. Mental-emotional stressors certainly trigger the activation of the stress response pathways, but physiological and lifestyle factors contribute to these physiological processes as well.

For anyone who has dealt with issues that are related to chronic fatigue has likely evaluated their hypothalamic–pituitary–adrenal (HPA) axis performance through a multi-point salivary test. The hormone Cortisol is measured in saliva when the samples are collected through predetermined intervals throughout a single day reveal one’s physiological resilience and metabolic reserve in response to daily stressors. HPA axis testing is a mainstay in the world of integrative, naturopathic, and functional medicine.

For the past 2 years, the world has existed under the constant shadow of COVID-19. To say that we have been “stressed” is an understatement. Mental-emotional stressors certainly trigger the activation of the stress response pathways, but physiological and lifestyle factors contribute to these physiological processes as well. Furthermore, inflammation due to infection provoke the adrenal glands to release cortisol to regulate the inflammatory response and support the immune system. In the case of COVID-19, the research cited below has shown that cortisol does not rise in response to the SARS-CoV-2 infection as expected. In fact, surprisingly, the opposite is true - cortisol levels drop in the presence of SARS-CoV-2, leaving the body vulnerable to escalating and unchecked inflammation, and predisposing the individual to the life-threatening adrenal crisis.

HPA axis dysfunction can occur under many types of chronic stressors; however, viral infections can trigger specific dysfunction within the HPA axis, leaving its host with chronic fatigue and weakness long after the initial infection has been resolved. Some of the latest research also takes a closer look at other endocrine organs such as the thyroid, hypothalamus, pituitary, pancreatic and gonadal tissue, and how each may be affected by the SARS-CoV-2 virus. In the last installment of this four-part series on long COVID, we will look at the mechanisms involved with the SARS-CoV-2 virus and the HPA axis, and what this means for COVID long-haulers.

SARS-CoV-2 and Adrenal Insufficiency

HPA axis dysfunction can occur under many types of chronic stressors; however, viral infections can trigger specific dysfunction within the HPA axis, leaving its host with chronic fatigue and weakness long after the initial infection has been resolved.

SARS-CoV-2 can influence cortisol output through three different pathways.

In a letter to the editor of the American Journal of Physiology-Endocrinology and Metabolism, Siejka postulates that adrenal insufficiency (AI) related to COVID-19 may occur for the following reasons: 1) hypophysitis and adrenalitis resulting from direct infection with the SARS-CoV-2 virus, leading to secondary or primary AI; 2) production of adrenocorticotropic hormone (ACTH) antibodies; and 3) critical illness-related corticosteroid insufficiency (CIRCI) [1]. It has been determined that the hypothalamus, pituitary, and the adrenal glands all have angiotensin-converting enzyme (ACE)2 receptors so direct infection of these organs is plausible. In fact, histological findings report focal necrosis and vasculitis of the small veins of the adrenal glands, and structural and functional damage within the hypothalamus and the pituitary in those who were infected with the SARS-CoV-2 virus [1].

According to the recent article published in Medical Hypotheses, the uncanny ability of SARS-CoV-2 to inhibit the host’s corticosteroid stress response is a means to evade the immune system [2]. SARS viruses have a unique mechanism to inhibit the activation of the stress response and prevent cortisol release by expressing a series of amino acids that mimic parts of the ACTH amino acid structure, a process that can be best described as molecular mimicry. What happens next is the immune system forms antibodies against both the coronavirus and ACTH, and the antibody-bound ACTH becomes completely ineffective at stimulating the release of cortisol, resulting in hypocortisolism [3]. It is postulated that the virulence of SARS-CoV-2 may be related to the degree of antigenic similarity between ACTH and its molecular mimic within the virus [2].

A condition referred to as critical illness-related corticosteroid insufficiency (CIRCI) occurs in patients with an acute stress response, leading to reduced cortisol levels that do not match the severity of the disease. CIRCI is presumed to occur in several critical conditions, including sepsis and septic shock, severe community-acquired pneumonia, acute respiratory distress syndrome, cardiac arrest, head injury, trauma, burns, and following major surgery [4]. Because of the mechanisms involved in suppressing the release of cortisol, Siejka recommends early use of steroids not only to replace what is deficient, but also because hydrocortisone protects against endothelial barrier dysfunction, which is strongly associated with COVID-19 [1].

Early Treatment of COVID-19 with Steroids to Inhibit Disease Progression

Early in the COVID-19 crisis, it was the general consensus that steroids given too early in the disease process might suppress the immune system’s ability to fight the infection and reduce viral replication. As noted above, antibodies are produced against ACTH during SARS-CoV-2 infection. These antibodies interfere with ACTH’s normal signaling to trigger cortisol production as part of the stress response. Lower cortisol levels then provide feedback to the hypothalamus and pituitary to increase the production of ACTH to release more cortisol. Instead, increased ACTH production increases ACTH antibodies that do nothing to fight the viral infection. It is proposed by both Siejka and Wheatland that if corticosteroids are administered early, shortly after the start of the infection, ACTH production and therefore antibody production toward ACTH would decrease, freeing up the immune system’s antibody response to fight against the virus rather than ACTH [1, 2]. The increase in exogenously-administered corticosteroids may also help fine-tune the inflammatory response early, which would keep tissue damage under control. Early intervention with lower potency steroids like hydrocortisone, may act as a replacement for what is missing due to the interference of cortisol production by the virus. Perhaps this proves the adage that, “an ounce of prevention is worth a pound of cure.”

Studies Related to SARS and Adrenal Insufficiency

One small study on 28 hospital patients demonstrated that adrenal response to infection with SARS-CoV-2 was unexpectedly decreased – patients had low plasma cortisol and ACTH levels consistent with central adrenal insufficiency. Lower plasma cortisol and ACTH levels were consistent with higher disease severity, suggesting a direct link between COVID-19 and impaired glucocorticoid response [3]. Interestingly, ACE2 receptors, the gateway for SARS-CoV-2 entry into cells, are expressed in the hypothalamus, pituitary and adrenal glands, allowing the virus to enter these tissues. Autopsy studies on patients who died from the SARS-CoV-1 infection showed evidence of the viral genome in hypothalamic tissue.

In a recent case study, a 51-year-old male presented to the emergency department complaining of two episodes of vomiting. He had received a positive COVID-19 test via polymerase chain reaction testing 10 days prior but was asymptomatic with stable vital signs and a normal chest X-ray at the time of diagnosis. No laboratory studies were done, and he was instructed to quarantine at home. When he presented to the ER, he was hypotensive with multiple electrolyte derangements that could not be substantiated by only two episodes of vomiting. Adrenal insufficiency was confirmed by low morning cortisol levels and an ACTH stimulation test. The patient was started on 20 mg of prednisolone daily with subsequent improvement in blood pressure and sodium levels [5].

In another case study, a 47-year-old male with a recent diagnosis of COVID-19, developed new onset central hypocortisolism in the convalescent phase of a mild case of COVID-19. He was sent to an isolation facility but returned to the hospital one week later due to a new onset seizure. The patient’s vital signs were normal, and he was well-oxygenated on room air. His bloodwork revealed elevated eosinophils and he complained of new onset persistent dyspepsia. Hypocortisolism was suspected and confirmed with a serum cortisol of 19 (normal range = 133-537 nmol/L) and an ACTH of 7.1 (normal range = 10.0-60.0 ng/L). He also presented with elevated thyroxine and thyroid stimulating hormone (TSH). This led his physicians to believe that the hypocortisolism was due to effects within the hypothalamic-pituitary pathways, affecting both adrenal and thyroid function [6].

SARS-Induced Endocrinopathy

The deleterious impact of SARS-CoV-2 on the various organs within the endocrine system are becoming clearer as further research reveals the far-reaching health consequences of the virus.

The deleterious impact of SARS-CoV-2 on the various organs within the endocrine system are becoming clearer as further research reveals the far-reaching health consequences of the virus. As we develop an understanding of the extent of these effects, we can better intervene with appropriate therapy. We understand from current research that SARS-CoV-2 can induce new onset or worsen existing conditions, such as diabetes mellitus, trigger hypocortisolism, and contribute to thyroid and reproductive aberrations [7]. The available data suggest that effects on endocrine tissues can occur either from direct viral damage or from immune-mediated mechanisms on endocrine tissues precipitated by the SARS-CoV-2 virus [7].

Diabetes mellitus increases the risk for the development of COVID-19 complications and adverse outcomes. In reviewing the effects of SARS-CoV-1, it was suggested that the virus could directly damage pancreatic cells that express ACE2 receptors, leading to a state of hyperglycemia, which reduces immune response and increases organ damage and systemic complications [8]. In a recent article in Endocrine, Mongioi et al hypothesized that patients with COVID-19 may be subject to virus-mediated pancreatic damage, resulting in the development of diabetes. It is uncertain at this point if the onset of diabetes is permanent or a transient effect of the virus that will eventually resolve with recovery from the infection [8].

Little is known about the effects of SARS-CoV-2 on thyroid function; however, some research has revealed a relationship between SARS-CoV-1 and central hypothyroidism secondary to hypothalamic-pituitary dysfunction resulting in low TSH. In secondary hypothyroidism, if the thyroid is not receiving the message from TSH to stimulate the production of thyroid hormones, T3 and T4 will also be low. SARS-CoV-1 did not directly invade the thyroid; however, tissue studies revealed injury to the follicular epithelium with an increase in cell apoptosis, suggesting that the damage was likely mediated by an immune response against the thyroid [8]. Direct damage to thyroid tissue could result in impaired function and a decrease in thyroid hormones and calcitonin levels as compared to controls. It appears that both primary and secondary hypothyroidism may be caused by the virus. The effects of COVID-19 on thyroid function appear to be transient and resolve shortly after recovery from the viral infection [7].

Though no evidence exists that SARS-CoV-2 infects the ovaries, increases in serum prolactin, follicle-stimulating hormone, and luteinizing hormone with a reduction in estradiol and progesterone levels was noted in SARS patients as compared to controls. We do know that ACE2 is highly expressed in testicular tissue and past studies have found tissue damage indicative of orchitis on autopsy of six patients who died with SARS-CoV-1. Tissue effects may also be representative of immune-mediated damage triggered by the presence of the virus [8]. Some researchers suspect that testicular tissue provides an additional site of infection and may increase viral load in males as compared to females.

The hypothalamic and pituitary tissue also have ACE2 receptors and can be sites of SARS-CoV-2 infection if the virus enters the brain. As previously mentioned, it is suspected that SARS-CoV-2 can enter the brain via the olfactory pathway where it gains access to the brain across the porous cribriform plate. The virus can then enter the hypothalamus fairly easily as the blood-brain barrier is permeable near this structure. Infection of the hypothalamus may result in hypophysitis (inflammation of the hypothalamus) and would have broad effects across the entire endocrine system.

Long COVID and Adrenal Insufficiency

Adrenal insufficiency tends to develop in COVID-19 patients during the late stage of the disease and appears to be secondary to hypophysitis or direct damage to the hypothalamus from the SARS-CoV-2 virus. In 2005, Leow et al explored the function of the HPA axis in 61 SARS-CoV-1 survivors by evaluating serum electrolytes, cortisol, ACTH levels, and 24-hour urinary-free cortisol three months after the acute infection. Adrenal insufficiency was defined as cortisol values <550 nmol/L 30 minutes after an ACTH stimulation test. Nearly 40% of patients tested had hypocortisolism and among them 83% had central adrenal insufficiency, which is secondary to ACTH deficiency [9]. Of those with hypocortisolism, 62.5% recovered within one year paralleled by the resolution of orthostatic hypotension and an overall improved sense of well-being. The majority of the patients in the study exhibited cortisol dynamics analogous to patterns seen in chronic fatigue syndrome, post-traumatic stress disorder, and fibromyalgia [9].

It is important to note that patients may also experience hypocortisolism due to treatment with dexamethasone to reduce inflammation during active infection. Treatment of COVID-19 with potent steroids to address the immunoinflammatory response to the infection may result in short-term adrenal insufficiency that may require evaluation and supportive care. In the 2005 study by Leow et al referenced above, the majority of the patients studied had not been treated with steroids during the course of their illness. Four of the six who had received high-dose parenteral glucocorticoids did not develop post-SARS hypocortisolism as demonstrated by the lack of prolonged suppression of the HPA axis as revealed in serial ACTH stimulation tests [9].

Addressing Long COVID through HPA Axis Support

Many of the symptoms of post-viral syndromes interfere with our ability to thrive, which indicates involvement of the autonomic nervous system (ANS), leaving us with orthostatic intolerance, cognitive dysfunction, muscle weakness, fatigue, dizziness, and heart rate abnormalities. Although isolating where some of these symptoms may be coming from is a starting point to treatment, it is necessary to consider the contribution of other organ systems to each dysfunction. Many of the symptoms associated with autonomic dysfunction may be related to the ability of the mitochondria to make energy and support metabolic processes. Involvement of the HPA axis with the sympathetic branch of the ANS contributes to maintaining adequate blood sugar and blood pressure, as well as inhibiting inflammation and supporting a balanced immune system response. An appropriate response of the HPA axis during an acute stressor is necessary for survival, but frequent and prolonged activation can alter the functional tone of the stress response reducing the ability of the HPA axis to respond efficiently and effectively [10].

Post-viral illness is difficult to address in that it cannot be cured by treating only one symptom or one system. Genetic susceptibility, nutritional status, and state of health prior to infection will likely play a role in the development of long COVID, and the supportive care to pull through the long-term sequelae of this virus will require a multi-pronged approach. Our ability to respond to stressors involves the sympathoadrenal system and the HPA axis, and interactions between these two systems play a central role in adaptation. Healthy function of the HPA axis is dependent on healthy mitochondria for steroid hormone conversion and an intact ANS to support a normal stress response. Long-term changes to the HPA axis may occur in response to the stress of an acute illness that has altered the metabolism of cortisol, leading to a reduced capacity to respond to stress [4]. To address the oncoming tidal wave of COVID-19 survivors who have ongoing symptoms, supporting the HPA axis through nutrition, supplementation, adaptogenic herbs, glandulars, and hydrocortisone if needed, will likely offer some relief. Options for support of the nervous system, immune system, and mitochondria have been outlined in parts one through three of this series.

Testing the HPA Axis

Genetic susceptibility, nutritional status, and state of health prior to infection will likely play a role in the development of long COVID, and the supportive care to pull through the long-term sequelae of this virus will require a multi-pronged approach.

Aside from infection with the SARS-CoV-2 virus, the stress of the pandemic itself has been extensive. Fear of infection, lockdowns, social isolation, financial instability, and emotional distress have taken a toll on our collective psyche. The extraordinary amount of stress that we have been under can certainly have lasting consequences in chronic activation of the stress response systems, leading to ongoing dysfunction of the HPA axis. For those who have been infected with the virus, early testing of the HPA axis offers another opportunity for intervention and recovery from COVID-19 and can be easily done at home through a multi-point salivary test measuring cortisol output throughout the day. As the above-referenced studies indicate, developing hypocortisolism is a real possibility after the infection with SARS-CoV-2 and may likely be a major contributor to the symptoms of long COVID. Testing for and addressing this issue is key to a full recovery.

In addition to multi-point cortisol measurements, ZRT Laboratory can also provide testing to assess melatonin levels, dehydroepiandrosterone sulfate (DHEA-S), high-sensitivity C-reactive protein (hsCRP), vitamin D, sex hormones, thyroid hormones, and neurotransmitters. Melatonin increases in response to darkness but may be compromised due to dysregulation within the circadian rhythm. In addition to regulating sleep, melatonin is a potent antioxidant that can help to neutralize reactive oxygen species produced during inflammation. DHEA-S functions in the brain and nervous system as a neurosteroid, is a potent immune-modulating hormone and functions as a counter-regulatory hormone to cortisol. The main neurobiological effects of DHEA-S in the brain include neuroprotection, neurogenesis, apoptosis, catecholamine synthesis and secretion, and antioxidant and anti-inflammatory effects. Measuring sex hormones and thyroid markers can provide much needed data that may help to address the symptoms associated with post-viral illness.

While an initial infection can resolve, it can leave behind an inflammatory footprint that propagates further damage. Measuring hsCRP can provide us with information regarding general inflammation and infection. hsCRP can be readily measured in a dried blood spot (DBS) sample alongside other cardiovascular and metabolic markers. Healthy vitamin D levels are associated with a robust and balanced immune response and can also be measured in DBS. ZRT Laboratory can also provide testing to assess neurotransmitters that impact mood, cognitive ability, and sleep. Neurotransmitters are responsible for functionally integrating the immune and endocrine systems, indicating that neurotransmitter imbalances often reach beyond the brain.

As we face the burgeoning issue of long COVID, the approach to treatment will involve addressing inflammation and dysregulation within the central nervous system, autoimmune issues, mitochondrial function, and hormone and HPA axis dysregulation. We have a long road ahead of us and there will likely be many who suffer from the long-term consequences of this pandemic – those who acquired the infection and those who simply lived through it. Our personal timelines may be forever referred to by pre-COVID and post-COVID events. My hope is that through the efforts of the many brilliant minds in medical research and through the practice of preventive and interventional therapies, we have learned how to better prepare for and respond to a novel virus. Early treatment for viral infections and immune system support are still important as coming up with new vaccines for each novel virus may not be practical, timely or safe. We may not be able to prevent infection, but by investing in our health every day, we may effectively support our recovery.

Tests to Consider

  1. Siejka A, Barabutis N. Adrenal insufficiency in the COVID-19 era. Am J Physiol Endocrinol Metab.2021;320(4):E784-E785
  2. Alzahrani AS, Mukhtar N, Aljomaiah A, et al. The impact of COVID-19 viral infection on the hypothalamic-pituitary-adrenal axis. Endocr Pract. 2021;27(2):83-89.
  3. Annane D, Pastores SM, Arlt W, et al. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a multispecialty task force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med. 2017;43(12):1781-1792.
  4. Hashim M, Athar A, Gaba WH. New onset adrenal insufficiency in a patient with COVID-19. BMJ Case Rep. 2021;14(1):e237690.
  5. Chua MWJ, Chua MPW. Delayed onset of central hypocortisolism in a patient recovering from COVID-19. AACE Clin Case Rep. 2021;7(1):2-5.
  6. Kothandaraman N, Rengaraj A, I Xue B, et al. COVID-19 endocrinopathy with hindsight from SARS. Am J Physiol Endocrinol Metab. 2021;320(1):E139-E150.
  7. Mongioì LM, Barbagallo F, Condorelli RA, et al. Possible long-term endocrine-metabolic complications in COVID-19: lesson from the SARS model. Endocrine. 2020;68(3):467-470.
  8. Leow MK‐S, Kwek DS-K, Ng AW-K, et al. Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clin Endocrinol (Oxf). 2005;63(2):197-202.
  9. Steenblock C, Todorov V, Kanczkowski W, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the neuroendocrine stress axis. Mol Psychiatry. 2020;25(8):1611-1617.


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