Endocrine System – American ME and CFS Society

COVID-19 and Chronic Fatigue Syndrome: An Endocrine Perspective

Abstract:

Patients recovering from COVID-19 may have persistent debilitating symptoms requiring long term support through individually tailored cardiopulmonary and psychological rehabilitation programs. Clinicians need to be aware about the likely long-term complications and their diagnostic assessments to help identify any occult problems requiring additional help. Endocrinological evaluations should be considered as part of the armamentarium in the management of such individuals with diligent cognizance about the involvement of the hypothalamo-pituitary-adrenal (HPA) axis, adrenals, and thyroid.

Source: Bansal R, Gubbi S, Koch CA. COVID-19 and Chronic Fatigue Syndrome: An Endocrine Perspective. J Clin Transl Endocrinol. 2021 Dec 3:100284. doi: 10.1016/j.jcte.2021.100284. Epub ahead of print. PMID: 34877261; PMCID: PMC8641402. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641402/ (Full text)

Characterization of Cortisol Dysregulation in Fibromyalgia and Chronic Fatigue Syndromes: A State-Space Approach

Abstract:

OBJECTIVE: Fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) are complicated medical disorders, with little known etiologies. The purpose of this research is to characterize FMS and CFS by studying the variations in cortisol secretion patterns, timings, amplitudes, the number of underlying pulses, as well as infusion and clearance rates of cortisol.

METHODS: Using a physiological state-space model with plausible constraints, we estimate the hormonal secretory events and the physiological system parameters (i.e., infusion and clearance rates).

RESULTS: Our results show that the clearance rate of cortisol is lower in FMS patients as compared to their matched healthy individuals based on a simplified cortisol secretion model. Moreover, the number, magnitude, and energy of hormonal secretory events are lower in FMS patients. During early morning hours, the magnitude and energy of the hormonal secretory events are higher in CFS patients.

CONCLUSION: Due to lower cortisol clearance rate, there is a higher accumulation of cortisol in FMS patients as compared to their matched healthy subjects. As the FMS patient accumulates higher cortisol residues, internal inhibitory feedback regulates the hormonal secretory events. Therefore, the FMS patients show a lower number, magnitude, and energy of hormonal secretory events. Though CFS patients have the same number of secretory events, they secrete lower quantities during early morning hours. When we compare the results for CFS patients against FMS patients, we observe different cortisol alteration patterns.

SIGNIFICANCE: Characterizing CFS and FMS based on the cortisol alteration will help us to develop novel methods for treating these disorders.

Source: Pednekar DD, Amin MR, Fekri Azgomi H, Aschbacher K, Crofford LJ, Faghih RT. Characterization of Cortisol Dysregulation in Fibromyalgia and Chronic Fatigue Syndromes: A State-Space Approach. IEEE Trans Biomed Eng. 2020 Mar 5. doi: 10.1109/TBME.2020.2978801. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32149617

A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients with Chronic Fatigue

Abstract:

Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome (CFS) are complex medical conditions with similar symptoms such as anxiety, fatigue, depression, headaches, muscle aches and joint pain. The etiology of both these syndromes is unknown. The objective of this study is to characterize FMS, both in the presence and in the absence of CFS, by analyzing variations in cortisol secretion patterns, timings, amplitudes, and the number of the underlying pulses as well as infusion and clearance rates.

The comparison is performed against matched healthy control subjects. We estimate the hormonal secretory events by deconvolving cortisol data using a two-step coordinate descent approach. The first step implements a sparse recovery approach to infer the amplitudes and the timings of the cortisol secretion events from limited cortisol hormone data. The main advantage of this method is estimating the cortisol secretory events using a system theoretic approach. The second step is to estimate the physiological system parameters (i.e. infusion and clearance rates). This approach has been verified on healthy individuals previously.

Our results show that the clearance rate of cortisol by the liver is relatively lower in patients as compared to the matched healthy individuals. This suggests that there is a relatively higher accumulation of serum cortisol in patients when compared to matched healthy subjects.

Source: Pednekar DD, Amin MR, Azgomi HF, Aschbacher K, Crofford LJ, Faghih RT. A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients with Chronic Fatigue. Conf Proc IEEE Eng Med Biol Soc. 2019 Jul;2019:6896-6901. doi: 10.1109/EMBC.2019.8857427. https://www.ncbi.nlm.nih.gov/pubmed/31947425

Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome

Abstract:

PURPOSE: The complex and varied presentation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has made it difficult to diagnose, study, and treat. Its symptoms and likely etiology involve multiple components of endocrine and immune regulation, including the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, and their interactive oversight of immune function. We propose that the persistence of ME/CFS may involve changes in the regulatory interactions across these physiological axes. We also propose that the robustness of this new pathogenic equilibrium may at least in part explain the limited success of conventional single-target therapies.

METHODS: A comprehensive model was constructed of female endocrine-immune signaling consisting of 28 markers linked by 214 documented regulatory interactions. This detailed model was then constrained to adhere to experimental measurements in a subset of 17 candidate immune markers measured in peripheral blood of patients with ME/CFS and healthy control subjects before, during, and after a maximal exercise challenge. A set of 26 competing numerical models satisfied these data to within 5% error.

FINDINGS: Mechanistically informed predictions of endocrine and immune markers that were either unmeasured or exhibited high subject-to-subject variability pointed to possible context-specific overexpression in ME/CFS at rest of corticotropin-releasing hormone, chemokine (C-X-C motif) ligand 8, estrogen, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone 1, interleukin (IL)-23, and luteinizing hormone, and underexpression of adrenocorticotropic hormone, cortisol, interferon-γ, IL-10, IL-17, and IL-1α. Simulations of rintatolimod and rituximab treatment predicted a shift in the repertoire of available endocrine-immune regulatory regimens. Rintatolimod was predicted to make available substantial remission in a significant subset of subjects, in particular those with low levels of IL-1α, IL-17, and cortisol; intermediate levels of progesterone and FSH; and high estrogen levels. Rituximab treatment was predicted to support partial remission in a smaller subset of patients with ME/CFS, specifically those with low norepinephrine, IL-1α, chemokine (C-X-C motif) ligand 8, and cortisol levels; intermediate FSH and gonadotropin-releasing hormone 1 levels; and elevated expression of tumor necrosis factor-α, luteinizing hormone, IL-12, and B-cell activation.

IMPLICATIONS: Applying a rigorous filter of known signaling mechanisms to experimentally measured immune marker expression in ME/CFS has highlighted potential new context-specific markers of illness. These novel endocrine and immune markers may offer useful candidates in delineating new subtypes of ME/CFS and may inform on refinements to the inclusion criteria and instrumentation of new and ongoing trials involving rintatolimod and rituximab treatment protocols.

Source: Morris MC, Cooney KE, Sedghamiz H, Abreu M, Collado F, Balbin EG, Craddock TJA, Klimas NG, Broderick G, Fletcher MA. Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome. Clin Ther. 2019 Mar 28. pii: S0149-2918(19)30112-2. doi: 10.1016/j.clinthera.2019.03.002. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30929860

High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology

Abstract:

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is a central regulator of stress response and its dysfunction has been associated with a broad range of complex illnesses including Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS). Though classical mathematical approaches have been used to model HPA function in isolation, its broad regulatory interactions with immune and central nervous function are such that the biological fidelity of simulations is undermined by the limited availability of reliable parameter estimates.

METHOD: Here we introduce and apply a generalized discrete formalism to recover multiple stable regulatory programs of the HPA axis using little more than connectivity between physiological components. This simple discrete model captures cyclic attractors such as the circadian rhythm by applying generic constraints to a minimal parameter set; this is distinct from Ordinary Differential Equation (ODE) models, which require broad and precise parameter sets. Parameter tuning is accomplished by decomposition of the overall regulatory network into isolated sub-networks that support cyclic attractors. Network behavior is simulated using a novel asynchronous updating scheme that enforces priority with memory within and between physiological compartments.

RESULTS: Consistent with much more complex conventional models of the HPA axis, this parsimonious framework supports two cyclic attractors, governed by higher and lower levels of cortisol respectively. Importantly, results suggest that stress may remodel the stability landscape of this system, favoring migration from one stable circadian cycle to the other. Access to each regime is dependent on HPA axis tone, captured here by the tunable parameters of the multi-valued logic. Likewise, an idealized glucocorticoid receptor blocker alters the regulatory topology such that maintenance of persistently low cortisol levels is rendered unstable, favoring a return to normal circadian oscillation in both cortisol and glucocorticoid receptor expression.

CONCLUSION: These results emphasize the significance of regulatory connectivity alone and how regulatory plasticity may be explored using simple discrete logic and minimal data compared to conventional methods.

Source: Sedghamiz H, Morris M, Craddock TJA, Whitley D, Broderick G. High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology. BMC Syst Biol. 2018 Jul 17;12(1):76. doi: 10.1186/s12918-018-0599-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050677/ (Full article)

Hair and salivary cortisol in a cohort of women with chronic fatigue syndrome

Abstract:

Hypocortisolism has been found in CFS patients in blood, urine, and saliva. It is unclear if hypocortisolism can also be demonstrated using long-term cortisol measurements, such as cortisol in hair. In addition, the interaction between the HPA axis and the immune system, both expected to play an important role in CFS, is unclear. The objective of the current study was to compare hair and salivary cortisol concentrations in a cohort of female CFS patients to those in healthy controls, and to test the effect of an interleukin-1 receptor antagonist (anakinra) on the HPA axis.

Salivary cortisol concentrations of 107 CFS patients were compared to 59 healthy controls, with CFS patients showing a decreased cortisol awakening response (4.2 nmol/L ± 5.4 vs 6.1 nmol/L ± 6.3, p = 0.036). Total cortisol output during the day did not differ significantly in saliva, but there was a trend to lower hair cortisol in a subset of 46 patients compared to 46 controls (3.8 pg/mg ± 2.1 vs 4.3 pg/mg ± 1.8, p = 0.062). After four weeks of treatment with either daily anakinra (100 mg/day) or placebo, there was a slight decrease of hair cortisol concentrations in the anakinra group compared to an increase in the placebo group (p = 0.022). This study confirms the altered dynamics of the HPA axis in a group of CFS patients, and for the first time shows that this might also be present for long-term cortisol measures.

Source: Roerink ME, Roerink SHPP, Skoluda N, van der Schaaf ME, Hermus ARMM, van der Meer JWM, Knoop H, Nater UM. Hair and salivary cortisol in a cohort of women with chronic fatigue syndrome. Horm Behav. 2018 May 25. pii: S0018-506X(17)30569-X. doi: 10.1016/j.yhbeh.2018.05.016. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29807037

Chronic fatigue syndrome possibly explained by lower levels of key thyroid hormones

Press Release: New research demonstrates a link between chronic fatigue syndrome (CFS) symptoms and lower thyroid hormone levels. Published in Frontiers in Endocrinology, the study indicates that CFS, a condition with unknown causes, can be explained by lower thyroid hormones — but may be distinct from thyroidal disease. This finding can be seen as a first step to finding treatment for a debilitating illness for which there is no recognized treatment.

Chronic fatigue syndrome is a common disease marked by lengthy spells of weakness, fatigue and depression. Its diagnosis is predominantly based on symptoms and on ruling out any underlying medical condition, rather than on laboratory tests and physical examination.

Interestingly, several symptoms resemble those of hypothyroidism — a condition where the thyroid gland does not produce enough thyroid hormone. In hypothyroidism, the body tries to encourage thyroid hormone activity by releasing more thyroid-stimulating hormone — however, this does not happen in patients with chronic fatigue syndrome.

This contrast in thyroid-stimulating activity led the study’s authors to hypothesize that chronic fatigue syndrome is caused by low activity of thyroid hormones in the absence of thyroidal disease.

Led by Dr. Begoña Ruiz-Núñez at the University Medical Center Groningen, The Netherlands, the researchers compared thyroid function and markers of inflammation between 98 CFS patients and 99 healthy controls. Remarkably, the CFS patients had lower serum levels of certain key thyroid hormones such as triiodothyronine (T3) and thyroxine (T4), but normal levels of thyroid-stimulating hormone.

Additional analyses indicated that CFS patients had a lower urinary iodine status and low-grade inflammation, which possibly mirrored the symptoms of patients with hypothyroidism. These CFS patients, however, had relatively higher levels of another thyroid hormone called “reverse T3” or rT3. This appeared to be due to a shift in hormone production, where the body preferred to convert T4 to rT3 instead of producing T3. The low T3 levels found in CFS patients coupled with this switchover to rT3 could mean that T3 levels are severely reduced in tissue.

“One of the key elements of our study is that our observations persisted in the face of two sensitivity analyses to check the strength of the association between CFS and thyroid parameters and low-grade inflammation,” says Dr. Ruiz-Núñez. “This strengthens our test results considerably.”

The researchers believe inclusion of patient information, such as duration of illness, would enable a correlation with their biochemical profiles. Further, even though the study demonstrates a link between chronic fatigue syndrome symptoms and low levels of key thyroid hormones, a definitive cause for CFS remains unknown.

If the study findings are confirmed by additional research, it may pave the way for a treatment for chronic fatigue syndrome.

Source: Eurekalert

Higher prevalence of ‘low T3 syndrome’ in patients with chronic fatigue syndrome: A case-control study

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disease with unknown cause(s). CFS symptoms resemble a hypothyroid state, possibly secondary to chronic (low-grade) (metabolic) inflammation. We studied 98 CFS patients (21-69 years, 21 males) and 99 age- and sex-matched controls (19-65 years, 23 males). We measured parameters of thyroid function, (metabolic) inflammation, gut wall integrity and nutrients influencing thyroid function and/or inflammation.

Most remarkably, CFS patients exhibited similar TSH, but lower FT3 (difference of medians 0.1%), TT4 (11.9%), TT3 (12.5%), %TT3 (4.7%), SPINA-GD (14.4%), SPINA-GT (14.9%), 24-hour urinary iodine (27.6%) and higher %rT3 (13.3%). FT3 below the reference range, consistent with the ‘low T3 syndrome’, was found in 16/98 CFS patients vs. 7/99 controls (OR 2.56; 95% CI=1.00 – 6.54). Most observations persisted in two sensitivity analyses with more stringent cut-off values for BMI, hsCRP and WBC.

We found possible evidence of (chronic) low-grade metabolic inflammation (ferritin and HDL-C). FT3, TT3, TT4 and rT3 correlated positively with hsCRP in CFS patients and all subjects. TT3 and TT4 were positively related to hsCRP in controls. Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels.

The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state. They resemble a mild form of ‘non thyroidal illness syndrome’ and ‘low T3 syndrome’ experienced by a subgroup of hypothyroid patients receiving T4 monotherapy. Our study needs confirmation and extension by others. If confirmed, trials with e.g. T3 and iodide supplements might be indicated.

Source: Begoña Ruiz-Núñez, Rabab Tarasse, Emar Vogelaar, Janneke Dijck-Brouwerand Frits Muskiet. Higher prevalence of ‘low T3 syndrome’ in patients with chronic fatigue syndrome: A case-control study. Front. Endocrinol. | doi: 10.3389/fendo.2018.00097 https://www.frontiersin.org/articles/10.3389/fendo.2018.00097/abstract

Neuroendocrine disorder in chronic fatigue syndrome

Abstract:

Background/aim: Neuroendocrine disorders are considered a possible pathogenetic mechanism in chronic fatigue syndrome (CFS). The aim of our study was to determine the function of the hypothalamic-pituitary-adrenal axis (HPA) and thyroid function in women of reproductive age suffering from CFS.

Materials and methods: The study included 40 women suffering from CFS and 40 healthy women (15-45 years old). Serum levels of cortisol (0800 and 1800 hours), ACTH, total T4, total T3, and TSH were measured in all subjects. The Fibro Fatigue Scale was used for determination of fatigue level.

Results: Cortisol serum levels were normal in both groups. The distinctively positive moderate correlation of morning and afternoon cortisol levels that was observed in healthy women was absent in the CFS group. This may indicate a disturbed physiological rhythm of cortisol secretion. Although basal serum T4, T3, and TSH levels were normal in all subjects, concentrations of T3 were significantly lower in the CFS group.

Conclusion: One-time hormone measurement is not sufficient to detect hormonal imbalance in women suffering from CFS. Absence of a correlation between afternoon and morning cortisol level could be a more representative factor for detecting HPA axis disturbance.

Source: Tomic S, Brkic S, Lendak D, Maric D, Medic Stojanoska M, Novakov Mikic A. Neuroendocrine disorder in chronic fatigue syndrome. Turk J Med Sci. 2017 Aug 23;47(4):1097-1103. doi: 10.3906/sag-1601-110. https://www.ncbi.nlm.nih.gov/pubmed/29154201

Depression, evening salivary cortisol and inflammation in chronic fatigue syndrome: A psychoneuroendocrinological structural regression model

Abstract:

INTRODUCTION: Chronic Fatigue Syndrome (CFS) is a poorly understood illness that is characterized by diverse somatic symptoms, hypothalamic pituitary adrenal (HPA) axis dysfunction and heightened inflammatory indicators. These symptoms are often exacerbated and accompanied by psychological distress states and depression. Since depression is known to be associated with HPA axis dysfunction and greater inflammation, a psychoneuroendocrinological (PNE) model of inflammation was examined in persons diagnosed with CFS in order to uncover underlying biopsychosocial mechanisms in this poorly understood chronic illness.

METHODS: Baseline data were drawn from two randomized controlled trials testing the efficacy of different forms of psychosocial intervention, and included psychological questionnaires, di-urnal salivary cortisol, and blood samples. Data were analyzed with structural equation modeling (SEM).

RESULTS: The sample (N=242) was mostly middle-aged (Mage=49.36±10.9, range=20-73years), Caucasian (70.1%), female (84.6%), highly educated (88.6% completed some college, college, or graduate program), and depressed (CES-D M=23.87±12.02, range 2-57). The SEM supporting a psychoneuroendocrinological model of immune dysregulation in CFS fit the data χ2 (12)=17.725, p=0.1243, RMSEA=0.043, CFI=0.935, SRMR=0.036. Depression was directly related to evening salivary cortisol and inflammation, such that higher evening cortisol predicted greater depressive symptoms (β=0.215, p<0.01) and higher pro-inflammatory cytokines (interleukin-2 [IL-2], IL-6, and tumor necrosis factor-alpha [TNF-α] levels (β=0.185, p<0.05), when controlling for covariates.

DISCUSSION: Results highlight the role of depression, cortisol and inflammation in possible biological mechanisms involved in the pathophysiology of CFS. Time-lagged, longitudinal analyses are needed to fully explore these relationships.

Source: Milrad SF, Hall DL, Jutagir DR, Lattie EG, Czaja SJ, Perdomo DM, Fletcher MA, Klimas N, Antoni MH. Depression, evening salivary cortisol and inflammation in chronic fatigue syndrome: A psychoneuroendocrinological structural regression model. Int J Psychophysiol. 2017 Sep 13. pii: S0167-8760(17)30162-9. doi: 10.1016/j.ijpsycho.2017.09.009. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28918107