# Adrenal Insufficiency Adrenal insufficiency is the insufficient release of adrenal hormones, primarily cortisol, from the adrenal glands. Traditionally, "adrenal insufficiency" refers to a measurable, clinical deficiency in cortisol. However, hypocortisolism, or a flat cortisol curve, may be more likely in patients with ME/CFS. # Testing for adrenal Insufficiency ## Blood Tests Biochemical testing, including a low morning cortisol level (<10 mcg/dL) and low ACTH levels, can aid in diagnosis. The cosyntropin stimulation test is confirmatory, with a peak cortisol response below 18.1 µg/dL being diagnostic. 4 point salivary cortisol testing can also be used to assess for cortisol levels over the course of the day. People with ME/CFS are more likely to have a flat cortisol curve, in insufficient elevation of morning cortisol. ## Salivary Tests **When to Collect Saliva Samples**: The standard times to collect salivary cortisol are immediately upon waking (around 8 AM), at noon, at 4 PM, and at bedtime (after 8 PM). If you have a regular sleep schedule but do not wake up at 8 AM, the recommended times are immediately upon waking, 4-5 hours after waking, 8-10 hours after waking, and at bedtime. Some will prefer to take the second sample 30 minutes after waking to measure the cortisol waking response. In this case, collect samples immediately upon waking, 30 minutes after waking, 4 hours after waking and 12 hours after waking. **Do not** eat or drink anything but water for 60 minutes prior to collection, drink alcohol within 12 hours of collection, or brush teeth within 30 minutes prior to collection. # Opioid Induced Adrenal Insufficiency **Opioid-induced adrenal insufficiency (OIAI)** is a condition resulting from the suppression of the hypothalamic-pituitary-adrenal (HPA) axis due to chronic opioid use. This suppression leads to decreased production of adrenocorticotropic hormone (ACTH) and subsequently cortisol. ## Mechanism Opioids suppress the hypothalamic-pituitary-adrenal (HPA) axis primarily through their action on the μ-opioid receptors (MOR) in the brain. Activation of these receptors inhibits the release of corticotropin-releasing hormone (CRH) from the hypothalamus and adrenocorticotropic hormone (ACTH) from the pituitary gland, leading to reduced cortisol production by the adrenal glands. The mechanism involves several pathways: **Direct Inhibition**: Opioids directly inhibit CRH neurons in the paraventricular nucleus (PVN) of the hypothalamus, reducing the secretion of CRH. **Noradrenergic System**: Opioids also inhibit the noradrenergic system, which normally stimulates CRH release. This inhibition further reduces the activation of the HPA axis. **Retrograde Signaling**: Opioids can induce retrograde signaling at hypothalamic synapses, leading to a persistent suppression of synaptic transmission through presynaptic μ receptors, which further dampens the HPA axis response. These mechanisms collectively result in a blunted cortisol response to stress and can lead to opioid-induced adrenal insufficiency (OIAI) in patients on long-term opioid therapy. This suppression is dose-dependent and more pronounced with higher opioid doses. ## Who is at Risk? Patients on long-term opioid therapy, particularly those on higher doses, are at increased risk. Studies have shown that the prevalence of OIAI ranges from 8.3% to 29% among chronic opioid users. The risk is higher with daily morphine milligram equivalents (MME) above 60 mg. ## Symptoms The clinical presentation of OIAI includes non-specific symptoms such as profound fatigue, musculoskeletal pain, weight loss, anorexia, postural hypotension, and abdominal pain. These symptoms can overlap with those of chronic pain and other conditions, making diagnosis challenging. ## Diagnosis Diagnosis of OIAI involves biochemical testing. A low morning cortisol level (<10 mcg/dL) and low ACTH levels are indicative. The cosyntropin stimulation test can confirm the diagnosis, with a peak cortisol response below 18.1 µg/dL being diagnostic. However, the exact cutoff values can vary, and newer assays suggest a lower threshold. ## Treatment The primary treatment for OIAI is the cessation or reduction of opioid use, which can lead to recovery of adrenal function in many patients. For those who cannot discontinue opioids, glucocorticoid replacement therapy is recommended. Hydrocortisone is typically used, with doses tailored to the individual patient's needs. Monitoring and managing symptoms during stress or illness is crucial to prevent [[Adrenal Crisis Management Guide|adrenal crisis]]. In summary, OIAI is a significant but under-recognized condition in patients on chronic opioid therapy. Awareness and appropriate diagnostic and therapeutic strategies are essential to manage this condition effectively. # Addison's Disease Addison’s disease is an autoimmune disease of the adrenal gland resulting in low cortisol levels. It needs to be ruled out in all cases of ME/CFS. Initial laboratory testing: - ACTH (drawn within 3 hours of waking such as 6-9 AM) - Serum cortisol (drawn within 3 hours of waking such as 6-9 AM) Abnormal laboratory results warrant further workup and treatment. # Adrenal Crisis Adrenal Crisis is a life-threatening emergency that can occur in patients with adrenal insufficiency. It is characterized by an acute deficiency of cortisol, leading to severe hypotension, shock, and multi-organ failure if not promptly treated. Patients with adrenal insufficiency should be educated on "sick day rules". Sick day rules include increasing glucocorticoid doses during periods of stress, illness, or surgery. They should also wear a medical alert bracelet. # Anatomy and Physiology ## HPA Axis The hypothalamic-pituitary-adrenal (HPA) axis is a critical endocrine system involved in stress response, energy metabolism, and immune regulation. It comprises three interconnected structures: 1. Hypothalamus: Releases corticotropin-releasing hormone (CRH) in response to stress or circadian cues. 2. Anterior pituitary: Produces adrenocorticotropic hormone (ACTH) upon stimulation by CRH. 3. Adrenal glands: Respond to ACTH by secreting cortisol, a key stress hormone. Cortisol regulates various physiological processes, including glucose metabolism, inflammation, blood pressure, and immune responses. Feedback inhibition ensures the system remains balanced, with cortisol signaling the hypothalamus and pituitary to downregulate CRH and ACTH production when levels are adequate. Dysfunction in the HPA axis, such as hyperactivation or insufficient cortisol production, is implicated in conditions like chronic stress, depression, chronic fatigue syndrome (CFS), and long COVID. These dysfunctions often manifest as fatigue, immune dysregulation, and abnormal stress responses. Let me know if you'd like to explore this further! ## ACTH **Adrenocorticotropic hormone (ACTH)** is a peptide hormone produced and released by the anterior pituitary gland. Its primary role is to regulate the function of the adrenal glands, particularly the production of cortisol, a key hormone involved in the stress response, metabolism, and immune regulation. ACTH secretion is stimulated by corticotropin-releasing hormone (CRH), which is released by the hypothalamus in response to stress or circadian rhythms. Once released into the bloodstream, ACTH binds to receptors on the adrenal cortex, triggering the synthesis and release of cortisol. Cortisol then provides feedback to the hypothalamus and pituitary to inhibit further CRH and ACTH production, maintaining hormonal balance. Deficiencies in ACTH can lead to conditions such as secondary adrenal insufficiency, characterized by low cortisol levels, fatigue, and immune dysfunction. In certain diseases, such as ME/CFS or Long COVID, ACTH production may be impaired due to inflammation, autoimmune damage, or infection, contributing to hypothalamic-pituitary-adrenal (HPA) axis dysfunction. ## Anterior Pituitary (Adenohypophysis) The adenohypophysis, also known as the anterior (front) pituitary gland, is a key endocrine organ that regulates various physiological processes through the production of hormones. It synthesizes and releases several critical hormones, including: - Adrenocorticotropic hormone (ACTH): Stimulates cortisol production from the adrenal cortex. - Growth Hormone (GH): Promotes growth, metabolism, and tissue repair. - Thyroid Stimulating Hormone (TSH): Regulates thyroid hormone secretion. - Prolactin: Influences milk production in lactating individuals. - Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH): Control reproductive functions, including ovulation and spermatogenesis. These hormones are secreted in response to signals from the hypothalamus, which integrates inputs from the body to maintain homeostasis. # Pathophysiology ## Autoimmune Destruction of HPA Axis as CFS Mechanism Patients with ME/CFS and Long COVID often exhibit low cortisol levels and impaired stress response systems. Autoimmune destruction of the glands involved in the HPA axis is one mechanism proposed to explain this dysfunction. Molecular mimicry has been identified as a key process in autoimmune destruction. For example, peptides from SARS-CoV-2, the virus responsible for COVID-19, share structural similarities with ACTH. This mimicry triggers the production of autoantibodies that not only target viral peptides but also cross-react with ACTH, leading to cortisol deficiency. The result is hypocortisolism and further dysregulation of the HPA axis. Pathogens that cause this immune system confusion are probably more likely to survive and reproduce and are there for selected for. In addition to molecular mimicry, inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), can suppress ACTH secretion by the pituitary. This suppression is further compounded by SARS-CoV-2’s ability to infect the adenohypophysis (anterior pituitary) and adrenal glands through ACE2 receptors, causing direct tissue damage and inflammation. Autoimmune destruction and the resulting HPA axis dysfunction are significant contributors to the fatigue, immune dysregulation, and systemic symptoms observed in both CFS and Long COVID. Understanding these mechanisms underscores the importance of targeted treatments to address hormone imbalances and mitigate symptoms. ## Infection of HPA Axis as CFS Mechanism Patients with ME/CFS and Long COVID have been demonstrated to have low cortisol levels and impaired stress response systems. Direct infection of the glands involved in the HPA axis is one possible mechanism for this. It is hypothesized that intracellular pathogens, such as EBV, CMV, and HSV exploit the lack of an effective blood-brain barrier in the anterior pituitary, facilitating infection. Additionally, SARS-CoV-2, the virus responsible for COVID-19, has been observed to infect tissues by using the ACE2 Receptor, which is highly expressed in the anterior pituitary and adrenal glands. This mechanism can lead to pituitary inflammation, secondary adrenal insufficiency, and disruptions in ACTH production. Such dysfunction contributes to the dysregulation of the HPA axis, exacerbating fatigue, immune hyperactivation, and other systemic symptoms characteristic of ME/CFS and Long COVID. ## Inflammation effect on HPA Axis as CFS Mechanism ME/CFS is associated with dysregulation of the HPA Axis partly driven by inflammatory cytokines. These signaling molecules, produced during immune activation, can inhibit key components of the HPA axis, leading to insufficient cortisol production and an impaired stress response. Tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are among the cytokines implicated in this process. These cytokines interfere with the release of corticotropin-releasing hormone (CRH) from the hypothalamus and suppress the secretion of ACTH by the anterior pituitary. Reduced ACTH levels diminish stimulation of the adrenal glands, resulting in low cortisol levels, a hallmark of HPA axis dysfunction in CFS. Chronic exposure to inflammatory cytokines not only suppresses cortisol production but also disrupts the normal feedback mechanisms that regulate the HPA axis. This prolonged inhibition exacerbates symptoms such as fatigue, immune dysregulation, and heightened sensitivity to stress. Understanding the role of inflammatory cytokines in HPA axis dysfunction highlights the potential for treatments targeting inflammation to restore hormonal balance and improve symptoms in patients with CFS. # Symptoms of Hypocortisolism The hormonal system requires energy to maintain blood sugar levels. This becomes necessary 2-4 hours after eating depending upon the meal and metabolic state. A meal of simple carbohydrates is more likely to create a steep drop in blood sugar that require a larger energetic burst to correct. - Adrenal insufficiency symptoms - Hangry - Worse if you go without food - Better with carbohydrates - Trouble dealing with stress - Adrenaline spikes - Waking around 2 am feeling anxious and/or hungry # Lifestyle Modifications Treat fasting intolerance by eating small meals every 3-4 hours. Eat balanced meals with a protein, fat and complex carbohydrate.  Avoid simple sugars which can cause insulin spikes with rebound hypoglycemia.  Treat nighttime hypoglycemia (which can present with nighttime awakenings around 2 AM, possibly with sweats and anxiety) with a hard boiled egg or similar small, high protein snack before bed.  For quick relief of hypoglycemia symptoms, dissolve ¼ to ½ tsp sugar under the tongue. # Herbal Treatments: Adaptogens Adaptogens are natural substances, typically derived from plants and herbs, that help the body adapt to stress and promote overall balance and resilience. They are believed to support the adrenal system and improve the body's ability to cope with physical, emotional, and environmental stressors. For individuals with ME/CFS, fibromyalgia and related disorders, adaptogens may offer a way to enhance energy levels, reduce fatigue, and improve overall well-being. Benefits of adaptogens in CFS may include: - **Stress reduction**: Adaptogens help modulate the body's stress response, potentially reducing cortisol levels and promoting relaxation. - **Increased energy**: Certain adaptogens may help combat fatigue and boost energy levels, making daily activities more manageable. - **Improved immune function**: By supporting the adrenal glands and overall resilience, adaptogens can enhance immune function, which is often compromised in chronic illnesses. - **Cognitive support**: Some adaptogens are known to enhance mental clarity and focus, which can be beneficial for those experiencing brain fog. - **Mood enhancement**: Adaptogens may help alleviate symptoms of anxiety and depression, which are common in chronic fatigue syndromes. Common adaptogens include: - **Ashwagandha**: Known for its calming effects and ability to reduce stress and anxiety, ashwagandha may help improve energy and stamina. - **Rhodiola Rosea**: This adaptogen is often used to combat fatigue and enhance physical performance, making it a good option for those experiencing exhaustion. - **Holy Basil (Tulsi)**: Holy basil can help reduce stress and support immune function, offering a sense of calm. - **Schisandra**: Known for enhancing endurance and reducing fatigue, schisandra also promotes mental clarity and focus. - **Ginseng (American Ginseng)**: American ginseng is known for boosting energy levels and improving overall well-being. - **Licorice Root**: Licorice can help support adrenal function and balance cortisol levels. It may also improve energy and alleviate fatigue, but should be used cautiously due to its potential to raise blood pressure. ### Licorice Licorice root can help repair the gut mucosal barrier, increase blood flow to the stomach, treat GERD, heal peptic ulcers, reduce gut inflammation, and support the gut microbiome. It also has anti bacterial, fungal and viral properties and has been used to treat H. Pylori, thrush, and herpes. It also has estrogenic effects in women and may be used to treat PEM and menopause symptoms. It can cause significant elevations in blood pressure so should be used under supervision of a physician. For people struggling with low blood pressure it can be helpful. DGL is licorice with the glycyrrhizin, which causes high blood pressure, removed. It’s unclear if DGL has the same benefit as licorice that has not been modified. The WHO recommends limiting glycyrrhizin intake to no more than 100 mg daily. There is roughly 10 mg glycyrrhizin in 1 g licorice root so 10 g would be about the daily limit. A typical dose of licorice, to treat asthma for example, is 1-5 g licorice root powder three times daily. ### Beneficial for - Gut lining repair - Mucositis - Antibacterial - H. pylori - Strep throat - Tooth decay and cavities - Antifungal (thrush) - Antiviral - HSV-1 - RSV - HIV - Anti-inflammatory - Acne - Eczema - Asthma - Arthritis - Blood pressure and adrenal support - Increases blood pressure - Reduces potassium - Helps the body more efficiently regulate cortisol (adaptogen) - PMS and Menopause - Appears to have estrogenic affects in women. - May be better than HRT for menopause - Antispasmodic ### Side effects - Reduced potassium - Increased BP - Edema Contraindicated in: hypertension, heart disease, kidney disease, pregnancy and nursing ### Dosing WHO recommends limiting glycyrrhizin intake to no more than 100 mg daily. DGL is free of glycyrrhizin but may not have the same health effects. Draxe.com recommends no more than 6-18 g daily if taking it every day. For GERD: Two 380 mg DGL tablets before meals For asthma: 1-5 g licorice root powder three times daily OR 2-5 mL tincture three times daily OR 250-300 mg licorice extract three times daily ## Other Supplements **Adrenaplex by Terre Naturally**, 1-2 capsules in the morning. Can take another at lunch if symptoms recur in the afternoon. This contains DHEA and pregnenolone so should be avoided in women with diabetes, hormonally sensitve cancers, or PCOS. (Ingredients: Adrenal glandulars, Vitamin C, B5, licorice, Tyrosine, pregnenolone, DHEA, rehmannia). It is not vegan.  **Adrenal Stress End by Enzymatic Therapy**, 1-2 capsules in the morning. Can take another at lunch if symptoms recur in the afternoon. This does NOT contain DHEA or pregnenolone. It is not vegan.  # Prescription Treatments: Hydrocortisone / Cortef Cortef (hydrocortisone) is a cortisol replacement prescription. Cortisol is high in the morning to help you wake up, and low in the evening, to help you fall asleep. You will mimic this by taking higher doses of Cortef in the morning. ## Safety Profile The prescription of hydrocortisone (Cortef) for subclinical adrenal insufficiency is controversial due to concern about adrenal suppression and hypocortisolism side effects. Dr. Teitelbaum recommends treatments of up to 25 mg per day of Cortef in select patients. He addressed concerns about adrenal suppression in a study examining his protocol on patients with ME/CFS and Fibromyalgia: > [!QUOTE] Quote > Toward the end of the (3 month long) study 7 active patients given cortisol (and 13 given cortisol placebo) had post study Cortrosyn stimulation tests done. In the 7 active patients, average cortisol levels increased or stayed the same after treatment. Average cortisol levels (mcg/dL) pre, ½ hour and 1 hour post Cortrosyn Intra-Muscularly (I.M.) were 14, 23 and 26 before treatment and 17, 23, and 26 after treatment. These results suggest that adrenal suppression did not occur with the low doses of cortisone used in the study. Based on this information indicating safety, the sound theoretical basis and personal experience with Cortef during my own illness I recommend Cortef for select patients based on symptoms. ## Dosing For ME/CFS using 5 mg tablets: Cortef (hydrocortisone) is a cortisol replacement prescription. Cortisol is high in the morning to help you wake up, and low in the evening, to help you fall asleep. You will mimic this by taking higher doses of Cortef in the morning. The standard times to take Cortef are at 8 AM, 12 PM and 4 PM. However, if you do not have a regular sleep schedule, or if you sleep at non-standard hours, you may need to modify these times. In general, take the first dose as soon as you wake up and take the other doses 4 hours after each other. Avoid taking any Cortef within 4 hours of going to bed. Titrate up to the next step every 3-7 days as tolerated. Go slowly if you are sensitive. Let me know if you experience side effects. Most common are trouble sleeping and anxiety, though these are unlikely on the small doses you will be taking. Benefits will likely be felt immediately once on a high enough dose. Step 1: 1/2 tablet first thing in the morning. Step 2: 1 tablet first thing in the morning and 1/2 tablet at noon. Step 3: 1 and 1/2 tablets first thing in the morning, 1 tablet at noon, and 1/2 tablet at 4 PM.