The Endocrine Blind Spot in ME/CFS and Long COVID Research: A Critical Oversight

By

Despite a growing body of research on ME/CFS and Long COVID, one critical system remains conspicuously underrepresented in scientific discourse: the endocrine system—particularly the hypothalamic-pituitary (HPA) axis, a central regulator of metabolism, stress response, and immune coordination.

This is not a minor oversight. It raises urgent questions about the direction and priorities of current research. Is the neglect of endocrine involvement rooted in persistent gaps in medical education? A lack of precise diagnostic tools? Or is it indicative of a broader systemic failure in how research agendas are set and funded? Whatever the cause, the consequences are tangible. The number of individuals affected by ME/CFS and Long COVID continues to climb, while progress in diagnostics and therapeutics remains frustratingly slow.

Crucially, the sidelining of hypothalamic-pituitary dysfunction stands in stark contradiction to decades of endocrinological evidence. The HPA axis plays a well-documented role in regulating energy production, muscle metabolism, sleep, and neuroimmune signaling—all of which are significantly disrupted in these conditions. A substantial body of literature, from foundational physiology to clinical endocrinology, provides a robust framework for immediate inquiry. Yet this knowledge is not being adequately translated into research frameworks, biomarker development, or clinical guidelines—representing a serious missed opportunity for therapeutic innovation.

This omission is no longer scientifically defensible. Functional MRI studies and other emerging tools have already demonstrated the complexity of hormonal regulation in post-viral syndromes, hinting at underexplored mechanisms with diagnostic and therapeutic potential. Still, the endocrine system remains largely peripheral in current models of ME/CFS and Long COVID.

To move beyond symptom cataloging toward mechanistic understanding and effective treatment, the endocrine system—especially the HPA axis—must be integrated as a core focus of research. Its role is not speculative; it is foundational. Ignoring it continues to hinder progress, delay relief for patients, and obscure the path to targeted, evidence-based care.

The time for marginalizing endocrine dysfunction in post-viral illnesses has passed. Re-centering the hypothalamic-pituitary axis within biomedical research is not only long overdue—it is essential. Millions of patients worldwide are depending on the scientific community to recognize and act on this long-neglected dimension of disease.

Key Hypothalamic-Pituitary Axes:

HPA Axis (Hypothalamic-Pituitary-Adrenal): Regulates cortisol production, essential for glucose homeostasis, energy mobilization, immune modulation, and the stress response.

HPT Axis (Hypothalamic-Pituitary-Thyroid): Controls the release of thyroid hormones (T₃ and T₄), which regulate basal metabolic rate, thermogenesis, cardiovascular function, and muscle metabolism.

HPS Axis (Hypothalamic-Pituitary-Somatotropic): Governs growth hormone (GH) secretion via GHRH, influencing protein synthesis, muscle growth, fat metabolism, and overall body composition.

Hormonal Influence on Skeletal Muscle:

Skeletal muscle is not only a major metabolic target of these hormonal signals but also functions as an endocrine organ in its own right. It releases myokines, signaling molecules that interact with the hypothalamus and other organs to coordinate systemic metabolism, appetite regulation, and immune responses—particularly in response to physical activity.

Hormonal Effects:

Anabolic (Muscle-building): Hormones such as GH, insulin, and testosterone promote protein synthesis, muscle hypertrophy, and nutrient uptake.

Catabolic (Muscle breakdown): Elevated cortisol, particularly during prolonged stress or inflammation, promotes muscle protein degradation to supply amino acids for gluconeogenesis.

Metabolic Regulation: Thyroid hormones are critical for oxidative metabolism in muscle cells, influencing mitochondrial function and endurance capacity.

Key Interactions in Energy and Glucose Homeostasis:

Energy Balance: The hypothalamus integrates signals from adipose tissue (leptin) and skeletal muscle (myokines) to regulate appetite, thermogenesis, and overall energy expenditure.

Glucose Control: Insulin, secreted by the pancreas, facilitates glucose uptake in muscle tissues—a process modulated by the broader hormonal environment established by hypothalamic-pituitary signaling.

 

References:

Muscle in Endocrinology: From Skeletal Muscle Hormone Regulation to Myokine Secretion and Its Implications in Endocrine–Metabolic Diseases
https://www.mdpi.com/2077-0383/14/13/4490

Metabolic Messengers: Thyroid Hormones
https://pmc.ncbi.nlm.nih.gov/articles/PMC7615975/

Skeletal Muscle Is an Endocrine Organ
https://www.sciencedirect.com/science/article/pii/S1347861319301343

Role of Myokines in Regulating Skeletal Muscle Mass and Function https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2019.00042/full

Hypothalamic-Pituitary-Adrenal (HPA) Axis
https://my.clevelandclinic.org/health/body/hypothalamic-pituitary-adrenal-hpa-axis

© 2000-2030 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9 

Comments

Post a Comment

Popular posts from this blog

Schnitzler Syndrome: A Rare Autoinflammatory Disorder

By
Schnitzler syndrome is a rare, chronic autoinflammatory disease characterized by chronic urticaria (hives), recurrent fever, joint pain, and monoclonal gammopathy (abnormal proteins in the blood). First described by Dr. Liliane Schnitzler in 1972 , this condition is often misdiagnosed, leading to years of untreated symptoms before a correct diagnosis is made. The case report, " A 58-Year-Old Woman With Urticaria, Fever, and Joint Pain " , describes a case that closely aligns with my own experience with this challenging disorder. Key Features of Schnitzler Syndrome Schnitzler syndrome presents with a characteristic set of symptoms, though not all patients experience them in the same way: Chronic Urticaria (Hives) – Persistent, non-itchy or mildly itchy red patches that do not respond to antihistamines. Monoclonal Gammopathy (IgM or IgG type) – Abnormal monoclonal immunoglobulin detected in the blood (most commonly IgM ). Recurrent Fever – Unexplained fever episodes, often...
Read more

Acute Flaccid Myelitis (AFM): Understanding the “Polio-like” Illness Affecting the Spinal Cord

By
Acute flaccid myelitis (AFM) is a rare but serious neurological disorder that primarily affects children and results in sudden weakness or paralysis in the limbs. Often referred to as a “polio-like” illness, AFM has drawn growing attention over the past decade due to its similarities with poliomyelitis and its seasonal spikes in reported cases. While AFM remains uncommon, its potential severity—and the uncertainty surrounding its causes—make it an important condition for clinicians, parents, and public health officials to understand. What Is Acute Flaccid Myelitis? AFM is a condition that affects the gray matter of the spinal cord , where it damages motor neurons responsible for muscle movement. This leads to acute, flaccid paralysis , meaning muscles become limp and weak, often without warning. The condition can progress rapidly, and in some cases, the weakness can become long-lasting or even permanent. Although its symptoms resemble those of poliovirus infection, AFM is not cau...
Read more

Dysferlin Protein: Key Roles, Genetic Locations

By
Image
The purpose of this article is to share and discuss the details of a new discovery, which is highlighted within: CRISPR-Cas9: A Breakthrough Tool to Repair the DYSF Gene The dysferlin protein plays an essential role in maintaining the integrity of muscle cell membranes, particularly in tissues that endure significant mechanical stress, such as skeletal and cardiac muscles . Encoded by the DYSF gene , dysferlin is indispensable for repairing damaged cell membranes after injury caused by muscle contraction or external forces. This article explores the main locations where dysferlin is produced, its role in muscle repair, and supportive nutritional and therapeutic strategies for individuals with dysferlin deficiency, such as those affected by dysferlinopathies (e.g., Limb-Girdle Muscular Dystrophy Type 2B or Miyoshi Myopathy). Currently, there is no definitive answer as to why the severity of dysferlin protein expression or depletion varies. Do pathogens play a role in the methylation o...
Read more