Adrenal Fatigue:Stress Dysfunction

Ryan Shelton, ND

Overview

• Stress

• Health effects of stress

• Adrenal response and HPA axis

• Diagnosis and testing

• Potential treatments

Stress

• Stress = Biosystemic expectations become unmatched to what is being currently observed or sensed adaptation response

• DiStress– Deleterious response to appraised mental, emotional, physical

demands; real or imagined• Eustress

– Enhancement of function; adaptation, physical improvements, learning

• Stressors– Stimuli which cause a stress response

• Manifestations– Worry, mood change, anxiety, depression, acne, pain, GI Sx,

dizziness, angina, tachycardia, appetite changes, sleep changes, social withdrawal, neglect, drug consumption, low libido, sexual dysfunction, increased PMS/menopausal Sx, nervous habits, death

Stressors

• Internal– Emotional

• Fear, anger, worry, sadness– Psychological

• Relationships, conflict between desires/beliefs, finances, negative attitudes, poor coping skills

– Biochemical• Hormone imbalances, hyper/hypoglycemia, poor dental/gingival

health, acute and chronic illness, physical exertion• External

– Thermal– Chemical

• Drugs• Environmental toxins

– Most are endocrine disruptors– Average adult has 91 identifiable toxins; 95-99% of those tested

have >10– Biological

• Infections

Stressors

• Stressors are cumulative and additive

• The greater the intensity of each stress, and the longer they last, the higher the cumulative allostatic load

Allostatic load

• Allostatic load is defined as the physiological consequences of chronic exposure to fluctuating or heightened neural or neuroendocrine response that results from repeated or chronic stress

• Four conditions that lead to allostatic load are:

– Repeated frequency of stress responses to multiple novel stressors

– Failure to habituate to repeated stressors of the same kind

– Failure to turn off each stress response in a timely manner due to delayed shut down

– Inadequate response that leads to compensatory hyperactivity of other mediators

Cost Of Stress

• Stress-related illness costs businesses an estimated $300 billion/yr– 20% of absenteeism– 40% of employee turnover– 55% of Employee Assistance Programs– 30% of disability costs

• These figures do not include productivity lost due to stress while at work, harassment, disability and drug plan costs due to illnesses caused by stress

Health Effects of Stress

• Clinical Manifestations– Fatigue (94%)– Nervousness/Irritability (86%)– Premenstrual tension (85%)– Salt craving (84%)– Depression (79%)– Chronic allergies (73%)– Apprehension (71%)– Chronic headache (68%)– Weakness (65%)– Lightheadedness (47%)– Poor memory (42%)– Insomnia (40%)

Health Effects of Stress

• Holmes and Rahe stress scale• Diseases directly related to stress

– Fibromyalgia– CFS– PTSS– RA– Autoimmune disorders– CA, AIDS, Infarct, pneumonia survival– Asthma, bronchitis– Cirrhosis– Obesity

Other clinical manifestations

• Environmental sensitivities, universal reactors, unresponsive hypothyroidism, slow/lack of recovery, persistently feeling unwell and overwhelmed, exercise intolerance, hypotension, salt craving, polydipsia, hypoglycemia, alternating constipation/diarrhea, frequent sighing, aggressive/negative language, morning fatigue

• Hollow face, hair/skin eczema, hyperpigmentation, dark circles under eyes, weight gain early, weight loss late, wet palms, PM edema

• Common sleep/wake cycle

– Tired at 8-10pm but resists going to bed

– Gets a 2nd burst by 11pm often lasting until 1-2am

– Most refreshing sleep 7-9am

Adrenal Glands

• Small glands (7-10g each) atop the kidneys with enormous blood supply for size

– As many as 60 arterioles may enter

• Total daily cortisol production of 10-15mg/d (Hertoghe 20-35mg/d)

• Females

– Major source of DHEA & testosterone

– After menopause, major source of E2 & progesterone

• Males

– Major source of DHEA

– Only appreciable source of E2 and progesterone

– After andropause, major source of testosterone

Cortical Adrenocytes regenerate and are displaced centripetally 100-140 days

Effects of cortisol

Effects of cortisol

• Counteracts insulin– Contributes to hyperglycemia & gluconeogenesis– Contributes to appetite and insulin resistance

• Decreases collagen/elastin synthesis from fibroblasts• Diuretic• Decrease immunocytokines, IgA, T cell proliferation• Reduces osteoblastic activity• Total cortisol exposure correlated with progressed atherosclerotic

plaques• Hippocampal atrophy; Decrease in neural plasticity• Increases BP by increasing sensitivity to Epi & Norepi• Can bind to mineralcorticoid receptors, but deactivated locally by

11-beta hydroxysteroid dehydrogenase type II to cortisone

• Connections between cortisol, epi/norepi, IL-6, adipocytes, and sickness behavior– Lethargy, depression,

anxiety, anorexia, sleepiness, hyperalgesia, reduction in grooming, and failure to concentrate

Cortisol,IL-6 & TNFα promote the quinolinate pathway away from serotonin

Aldosterone

• Stimulated by increase in plasma angiotensin II, ACTH, or potassium

• Increases reabsorption of sodium (chloride) and water and the excretion of potassium in renal collecting ducts and distal convoluted tubules

Epi/Norepi

• Produced by medullary chromaffin cells– Part of sympathetic nervous system– Released directly into systemic circulation

• 80% Epi, 20% Norepi– Epi more in emotional, Norepi more in physical pain

• Increases heart rate, force of contraction, blood pressure• Dilates bronchioles, increases respiration rate• Liberation of nutrients for muscles, dilates blood vessels for

muscles• Increases pro-inflammatory cytokines IL-6 & TNFα• Tremors, hypervigilance, anxiety

Stress

• General Adaptation Syndrome– Alarm

• Flight or fight response• Production of epi/norepi• Discharge of stored cortical

fat granules– Resistance

• Production/accumulation of cortical fat granules

• Recruitment of more resources to cope with persistent stressor

– Exhaustion• Resources eventually

depleted• Depletion of cortical fat

granules• Initial autonomic symptoms

may reappear

PTSD

• Shalev AY, et al. Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part I: HPA axis responses. Int J Neuropsychopharm. 2008 May;11(3):365-72.

• Videlock EJ, et al. Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part II: the adrenergic response. Int J Neuropsychopharm 2008 May;11(3):373-80.

• Pervanidou P. Biology of post-traumatic stress disorder in childhood and adolescence. J Neuroendocrin. 2008 May;20(5):632-8.

Adrenal hypertrophy/atrophy

• Several studies have shown hypertrophy and hyperplasia of adrenal glands subjected to chronic stress– Adrenal gland enlagement may be a sign of cumulative lifetime depression

• Left adrenal gland>right adrenal gland hypertrophy in suicide victims; R/L hemisphere decoupling; Right hemisphere holistic/creative/spacial awareness, negative affect/fear

• Primary chronic adrenocortical insufficiency (Addison’s disease)– Low cortisol levels which do not respond to ACTH– Autoimmune disorders, space occupying lesions (metastases, lymphomas),

hemorrhage, ACTH resistance, CBP polymorphisms, amyloid, sarcoid, hemochromatosis

• Secondary adrenocortical insufficiency– Decrease in ACTH (or CRH) production– Pituitary macroadenoma, craniopharyngioma, tuberculosis, sarcoidosis,

lymphocytic hypophysitis, head trauma, aneurysms, postpartum pituitary necrosis (Sheehan’s syndrome), pituitary apoplexy, metastases, traumatic brain injury; also mutations in pro-opiomelanocortin gene, decreased ACTH response to CRH

• Infections causing adrenocortical insufficiency– HSV, CMV, HIV, echovirus, tuberculosis, histoplasma, cryptococcus

• Rx causing adrenocortical insufficiency– Glucocorticoids, etomidate, ketoconazole, suramin, metyrapone,

aminoglutethimide, and mitotane

• Compensatory growth occurs through nervous system, not increase in ACTH

• May also be the mechanism through which environmental toxins disrupt the HPA axis

• In conditions of chronic stress the adrenal cortex undergoes

an adaptation that allows the hypersecretion of glucocorticoids to occur even without the increment of ACTH

Addison’s comparison

• Autoimmune causes 70-90% of primary deficiency

• 5-6 in 100,000; white non-Hispanic most common

• No Sx until adrenal cortex 90% compromised

• Progression of pathophysiology• Excess…then deficiency

– Subclinical Cushing’s also has been defined

• Opposite circadian rhythm • Reticularis zone first to atrophy• Adrenal cortex is particularly susceptible to

fibrosis and fatty degeneration when challenged by stress, toxicity, infection

• Low vagal tone• Responsiveness of HPA declines with age

– Endopeptidase activity declines with age

• Lifespan or age of cortical subcapsular stem cells

– Hayflick’s limit, accumulation of lipofuscin

– Modern day lions• Other terms

– Subclinical hypoadrenia, hypoadrenocorticism, minor Addison’s, adrenal fatigue, adrenal insufficiency, neurasthenia, functional hypoadrenia, adrenocortocal insufficiency

Cortisol reduces production of entire POMC precursor

Clinical Diagnosis

• Sx in Hx– Many questionnaires also available

• Physical exam– BP drops by 10mm/hg upon rising from a lying position– Pupil test

• Iris does not hold contraction– Sergant’s White Line Sign

• White line, not red, when line drawn on abdomen by blunt object– Rogoff’s Sign

• Tenderness when posterior 10-12 ribs percussed– Cold-face test– Cervical lymphadenitis– Abdominal tenderness with palpation– Commonly occurs with hypothyroidism

Laboratory Diagnosis

• Consider adrenal cortex, ACTH, and steroid 21-hydroxylase autoantibodies

• Neuropeptide Y also increases with stress; Cytokine testing? • Na/K ratio <30 may indicate adrenal insufficiency• Plasma cortisol

– Total– 8:00am 2-25mcg/dl (optimal 15-22mcg/dl)– 4:00pm 3-16mcg/dl (optimal 10-14mcg/dl)– Stimulation >18mcg/dl– Most doctors will treat if level is in bottom 1/3 of ref range– One study recommends Tx if random morning cortisol <13mcg/dl– Many doctors will treat if cortisol levels do not double within 30

mintues• 24 Urine

– 23-195mcg/24hr– Most doctors will treat if level is in bottom 1/3 of ref range

Random vs Stimulation

Laboratory Diagnosis

• Saliva testing considered gold standard

• One day collection of four vials

• Can have compliance/collection issues

• Physical integrity/uncontrollable vs controllable

Normal circadian rhythm

Common patterns

Potential Treatments

• Lifestyle changes, Lifestyle changes, Lifestyles changes

• Nutrition• Nutraceuticals• Glandular extracts• Botanicals• HRT

• Differs based on phase of General Adaptation Response curve

Lifestyle changes

• Normalize sleep schedule

• Music therapy

• Dancing

• Sex

• Massage therapy

• Yoga

• Relaxation response exercises

• Identification of Good/Bad agents

• Assessment/Learning coping skills

• Avoidance of stimulants/drugs/ETOH

• Weight loss

• Clinical detoxification of endocrine disruptors

Nutrition

• Avoid refined carbs• Increase proteins with healthy fats• Small, frequent meals; Never skip breakfast• Salt• Identify and remove food allergies• Foods high in B vitamins• Foods high in minerals

Alarm phase Tx

• Biofeedback, Emotional Freedom Technique

• Anti-inflammatory agents

• Nutraceuticals

– Magnesium, Vitamin B12, Folic acid, Vitamin B6, Fish oil, Inositol, DHEA, L-lysine with L-arginine, L-tryptophan

• Botanicals

– Passiflora, Withania, Hypericum, Valerian, Eschscholzia, Corydalis, Leonurus, Melissa, Cimicifuga, Humulus, Piper, Scutellaria

Resistance phase Tx

• Nutraceuticals– Phosphatidyl serine, L-tyrosine, L-theanine

• Pineal tetrapeptide Ala-Glu-Asp-Gly• Consider potassium supplementation and restricting sodium• Dark chocolate 40g/d• Botanicals

– Aromatherapy– Panax sp, Bacopa monniera, Evolvulus alsinoides, Gingko biloba,

Hypericum, Blupleurum chinense, Schisandra chinensis, Withania somnifera, Cordyceps sinensis, Eleutherococcus senticosis, Codonopsis pilsula, Rhodiola rosea, Emblica officinalis, Ocimum sanctum, Rosmarinus, Curcumin Magnolia and Phellodendron extract

• Hormones– DHEA, Oxytocin, Melatonin, Vitamin D

Exhaustion phase Tx

• Vitamin C, Vitamin B5• Increase salt; watch high potassium foods, esp in the

morning– Molasses, bananas, dried fruit, avocado, melons, yogurt,

figs, potatoes, orange juice, beans• ACE glandulars• Glycyrrhiza• Tripterygium wilfordii• DHEA, Estradiol, Testosterone• Rx

– Cortisone, hydrocortisone

Prognosis

• Must be compliant with diet/lifestyle changes

• Hormones which may aggravate cortisol deficinecy

– Melatonin, GH, Thyroid

• Mild

– 6-9 mos

• Moderate

– 12-18 mos

• Severe

– 15-24+ mos

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