Stress, Fatigue and The Adrenals www.drtomsalchemy.com Stress, Fatigue and The Adrenals Tom Archie, MD St Luke’s Wood River Family Medicine

When My Patients Visualize Stress…

When I Visualize Stress

Outline of this Presentation Differential Diagnosis of Fatigue Hypothalamic– Pituitary – Adrenal Axis Physiology of Chronic Stress Chinese Medicine Relaxation Techniques Four Cases Supplements Summary

Fatigue Differential Diagnosis Depression, anxiety, anemia, thyroid disorder, insomnia, infection, sleep apnea, alcohol overuse, mitochondrial dysfunction, heart failure, menopause, pregnancy, domestic or workplace abuse, celiac, irritable bowel syndrome, inflammatory bowel disease, medications, autoimmune disease, hypogonadism, B12 deficiency, malnutrition, electrolyte abnormality

Tests that can Help Narrow the Differential Diagnosis List Complete blood count Electrolytes, liver enzymes, urinalysis Thyroid assessment* Serum or salivary cortisol, DHEA-Sulfate, 17-OH progesterone Questionnaires Beck’s Depression Index Metagenics Stress IdentiT Protocol Medical Symptoms Questionnaire

If all you have is a Hammer Everything looks like a Nail - Look Before You Leap - Don’t jump from symptom of Fatigue to Thyroid Adrenal Candida Depression Cancer Without Considering and Evaluating Thoroughly

Chronic Fatigue Syndrome Four or more of the following symptoms that persist or recur during 6 or more consecutive months of illness and that do not predate the fatigue: Impaired short-term memory or concentration Sore throat Tender lymph nodes Muscle pain Multijoint pain without swelling or redness Headaches of a new type, pattern, or severity Unrefreshing and/or interrupted sleep Postexertion malaise lasting more than 24 hours Exclusion criteria: Active, unresolved or suspected disease that is likely to cause fatigue Psychotic, melancholic, or bipolar depression (but not uncomplicated major depression) Psychotic disorders, Dementia, Anorexia or bulimia nervosa Alcohol or other substance misuse Severe obesity

Major Depression Five or more of the following symptoms during the same 2-week period and one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Depressed mood (sad, empty, irritable or tearful most of most days Loss of interest or pleasure in most activities on most of most days Change in Weight of >5% in a month or change in appetite Insomnia or hypersomnia nearly every day Psychomotor agitation or retardation nearly every day (others observe restlessness or slowing down) Fatigue or loss of energy nearly every day Feelings of worthlessness or inappropriate guilt most days Difficulty thinking/concentrating, or indecisiveness most days Recurrent thoughts of death or of suicide without specific plan Clinically significant distress or impairment in social, occupational, or other function Not due to the direct physiological effects of a substance abuse or medical condition       

Fibromyalgia Widespread body pain present for at least 3 months Both sides of the body Above and below the waist (low back considered below waist) Includes axial skeletal pain (cervical spine, anterior chest, thoracic spine or low back pain) Strongly tender 11 of 18 tender points (9 bilateral) Occiput - suboccipital muscle insertions Low cervical - anterior aspects intertransverse spaces C5/7 Trapezius - midpoint of the upper border Supraspinatus – origins near the medial border of scapula Second rib - upper lateral to the second costochondral junction Lateral epicondyle - 2 cm distal to the epicondyle Gluteal - outer quadrants of buttocks in anterior fold of muscle Greater trochanter - posterior to the trochanteric prominence Knee - medial fat pad proximal to the joint line Acupuncture: GB20,BL10,GB21,SI13,KI27,LI10,BL53,GB30,LR8

Mayo Clinic on “Adrenal Fatigue” www.mayoclinic.com May 2010 “Proponents of the adrenal fatigue diagnosis claim this is a mild form of adrenal insufficiency caused by chronic stress. The unproven theory behind adrenal fatigue is that your adrenal glands are unable to keep pace with the demands of perpetual fight-or-flight arousal. As a result, they can't produce quite enough of the hormones you need to feel good. Existing blood tests, according to this theory, aren't sensitive enough to detect such a small decline in adrenal function — but your body is. It‘s frustrating to have persistent symptoms your doctor can't readily explain. But accepting a medically unrecognized diagnosis from an unqualified practitioner could be worse. Unproven remedies for so-called adrenal fatigue may leave you feeling sicker, while the real cause — such as depression or fibromyalgia — continues to take its toll.” Lacking in curiosity – Excessive in sarcasm

Adrenal Fatigue It’s not a Diagnosis - It’s a Function

Functional Medicine Matrix www.functionalmedicine.org

Perspective “Adrenal Fatigue” is not a standard medical diagnosis Therefore often dismissed by doctors Closest is “Adrenal Insufficiency” which is of much greater pathology and less common Inherited deficiency of enzyme needed to make adrenal hormones “Adrenal Fatigue” is a real and common phenomenon, but the term is often misused to encourage purchase of supplements instead of lifestyle changes.

Perspective “Adrenal Fatigue” describes the same process known as “chronic stress” Elevated cortisol in response to stress Can lead to depression Depression, Chronic Fatigue, and Fibromyalgia have a common root = prolonged elevated cortisol due to chronic stress Term “Adrenal Fatigue” coined by James Wilson, ND in 1990s

Perceived Stress Origin Timing Physical, metabolic, psychological, emotional Timing Acute and short lived versus Chronic, persisting, and unrelenting Section that follows credited to excellent chapter by Michael Lumpkin, PhD Lumpkin M. The Hypothalamic Pituitary Adrenal Axis. Textbook of Functional Medicine. Ed. Jones D. Institute for Functional Medicine. 2005

Stressors (Extensive research citations exist for the stressors listed below.) Sleep deprivation Financial stress Poverty Conflict (interpersonal, business) Persecution (domestic violence, incarceration) Death Divorce Moving/Relocating Attachment to Emotional Responses to Events Chronic Pain Chronic Illness

Hypothalamic Pituitary Adrenal Axis Cerebral Cortex Hypothalamus Pituitary Adrenal sits on Kidney

Stress Response - Hypothalamus Endocrine System’s Command Center Monitors neuronal, hormonal, metabolic and immune signals within the body compares them with Signals from receptors for temperature, pain, pressure, electrolytes blends this information with Higher cortical brain’s state of mind Fear, depression, agitation, anger, humor, contentment

Hypothalamus Produces “master” hormones called Releasing Hormones Communicates to Pituitary Gland Corticotropin Releasing Hormone – “CRH” (Adrenal) Thyrotropin Releasing Hormone (Thyroid) Prolactin Releasing Hormone (Breast) Gonadotropin RH LH and FSH - Testes, Ovary Growth hormone – skeletal/muscle growth, liver effect on sugar levels

Releasing Hormones Messages to Pituitary gland (intermediary for the other endocrine organs) Stress response, reproduction, metabolism (including thyroid), growth regulation, lactation, balance of water/electrolytes Regulates feeding, appetite, drinking, sex behaviors, emotions, hormonal rhythms

Event Data mixes with Emotional Response Cortex – higher brain Observes factual data from events Sends this via neurons to hippocampus & amygdala Hippocampus Learning and memory transferred to long term memory Amygdala Emotional responses are ATTACHED to factual info The Root of Suffering is the Attachment to Emotions We often confuse our emotional response to an event with the data about the actual event And We hold tightly to our attachment to our emotions Problem is not the emotion – it is the attachment to the emotion.

Biofeedback Hippocampus and Amygdala send neurons that converge on Hypothalamus In response to a blend of sensory information and emotional assignment to that data, Hypothalamic Releasing Hormones produce body changes Neurons from Hypothalamus also project up to higher cortical brain This way, individual can notice changes in arousal Respiratory rate, muscle tremor due to fight/flight hormones, alertness, body temperature, sweating, cold hands, dry mouth, changes in appetite and thirst, bowel discomfort Individual can CHOOSE to observe and act to change the response – this is natural Biofeedback

Hypothalamic Pituitary Adrenal Axis Cerebral Cortex Hypothalamus Pituitary Adrenal sits on Kidney

Hypothalamic Pituitary Adrenal Axis Corticotropin Releasing Hormone (CRH) Pain, trauma, infection, low blood pressure, exercise, low blood sugar, grief, loss, anger, fear causes hypothalamus to release CRH Anterior Pituitary responds by secreting Adrenocorticotropic Hormone (ACTH) Also called “Corticotropin”

ACTH – Adrenocorticotropic Hormone (aka Cortitropin) Turns cholesterol into adrenal steroids First into Pregnenolone, then by adrenal zone…into… Mineralo-corticosteroids (aldosterone) Electrolyte balance – salt reabsorption in kidney Gluco-corticosteroids (cortisol) Glucose regulation, immune suppression Androgenic steroids Androstenedione >Testosterone > Estrogens DHEA-Sulfate

Cortisol Stress increases metabolic demand Cortisol ensures adequate glucose and O2 to vital organs Brain, heart, lung, muscle Cortisol helps aldosterone Increase renal sodium reabsorption Allows increased blood volume

CRH > ACTH > Cortisol release Normal response to acute stress Cerebrum, hippocampus, amygdala > hypothalamic release of Corticotropin Releasing Hormone Cortisol rises until concentration high enough to produce negative feedback to hippocampus and thus to the hypothalamus to reduce CRH secretion - no prolonged cortisol excess Abnormal condition – prolonged stress Damage and death to negative feedback neurons in the hippocampus that help reduce CRH - sustained cortisol elevation Sapolsky RM et al. Endocr Rev. 1986;7:284-301 Stress > Adrenal Medulla produces Epinephrine & Norepinephrine > leads to ACTH release by Pituitary Additional release of cortisol

Prolonged Stress – Cortisol Cortisol rises with acute stress, then drops Cortisol stays high with chronic stress “I feel stressed most days.” After variable period of time (years) cortisol then drops to low levels “I feel fatigued most days.” Time to get to a low cortisol depends on individual’s constitution and type of stressors and frequency of exposure to stressors

Chronic Stress Prolonged Elevated Cortisol Increasing glucose levels Fat redistributes From thigh/buttocks to abdomen & lower neck Insulin resistance, fluid retention, high blood pressure Decline in musculoskeletal quality and function Proteolysis of muscle, bone, connective tissue Inhibits protein formation Orth DN, Kova WJ. The Adrenal Cortex. Williams Textbook of Endocrinology. 9th Ed. 1998:517-664.

Chronic Stress- Immune Dysfunction Reduced number & function of… Lymphocytes, eosinophils, basophils, monophils, macrophages, neutrophils Reduced production of immune cell signaling molecules Reduced antibody production Increased frequency of infectious disease Munck A et al. Endocr Rev. 1984;5(1):25-44

CRH and Adrenaline Corticotropin Releasing Hormone increases sympathetic (fight/flight) and reduces parasympathetic (calming) outflow from brain and spinal cord Increases epinephrine & norepinephrine (NE) from adrenal medulla Which further increases ACTH secretion by pituitary Increases NE & neuropeptide Y in the…. Heart, peripheral vessels, kidney, lung, pancreas, GI tract, testicles, ovaries Whole body effects

CRH and Adrenaline Result of increased CRH release by hypothalamus Increased pulse, heart contraction strength, blood pressure, respiratory rate, liver release of glucose and fatty acids, kidney secretion of anti-diuretic hormone, and blood volume Other effects of chronic stress/cortisol/CRH Thyroid function decreased Reproductive hormones disrupted

CRH, Adrenaline, and the Gut Gastrointestinal effects Stomach Reduced gastric contractility Reduced gastric emptying Colon Increased colon motility Rapid transit times Poor absorption of nutrients and water Bloating, fullness, diarrhea, cramps, exacerbation of IBS and Crohn’s Disease Tache Y et al. Am J Physiol Gastrointest Liver Physiol. 2001;280:G6173-77

CRH, Adrenaline, and the Gut Persistent stress reduces growth of probiotic bacteria (good bacteria) Lactobacillus Bifidobacteria And increases growth of potentially pathologic bacteria E. Coli Clostridia Enterobacter Lizko NN et al. Nahrung. 1984;28:599-605

Adrenal Fatigue Observations on Physical Exam Achilles' tendon reflex slow, low amplitude Slow pupillary reflexes General quality of integument is poor Ridged nails Hair thinning Creased/lined fingerprints Pale line above vermillion border No citation – observation shared with other physicians following this topic

Prolonged CRH = Depression CRH injected into animals’ brains Increased locomotor activity (escape) Startle response Anxiety Stress-induced fighting (increases with dose) Reduced appetite, avoidance of unfamiliar or threatening locations Sutton RE et al. Nature. 1982;297:331-33 Lenz HG et al. Horm Metab Res. 1987;16(suppl):17-23 These are the features of human depression

Prolonged CRH = Depression Depressed humans have sustained 24hr elevations of cortisol Depression pattern is blocked with CRH receptor blockers in experimental animals CRH receptor blocker drug named “Antalarmin” Chrousos GP, Gold PW. JAMA. 1992;267(9):1244-52 Habib K et al. PNAS. 2000;97(11):6079–6084

High HPA Axis Activity Low HPA Axis Activity (Elevated Cortisol) High HPA Axis Activity Low HPA Axis Activity (Elevated Cortisol) (Low Cortisol) Chronic Stress Melancholic Depression Anorexia Type 2 Diabetes Syndrome X Premenstrual Syndrome Adrenal Insufficiency Chronic Fatigue Synd Fibromyalgia Postpartum Depression PTSD Rheumatoid Arthritis exacerbation Chrousos GP, Gold PW. JAMA. 1992;267(9):1244-52

Depression/Anxiety & Heart Health Depression and anxiety increase the risk of death after heart attack and can lead to diabetes Exercise works as well as pharmaceutical drugs for depression at 4 months Drugs worked more quickly but effects equal at 4 months Blumenthal JA et al. Effects of Exercise Training on Older Patients with Major Depression. Arch Intern Med. 1999;159:2349-2356. Frasure-Smith N, Lesperance F. Depression and Anxiety as Predictors of 2-Year Cardiac Events in Patients With Stable Coronary Artery Disease. Arch Gen Psychiatry. 2008;65(1):62-71 Carney RM, et al. Depression and five-year survival following acute myocardial infarction: a prospective study. Journal of Affective Disorders, 2008. doi:10.1016/j.jad.2007.12.005

Emotion and Heart Health High levels of anger 3.15-fold increase in future heart disease Dose-dependant (more anger = more risk) Kawachi I et al. Circulation. 1996;94:2090-95 Strong experience of anxiety 3.2-fold increase in heart attack risk Kawachi I et al. Circulation. 1994;90:2225-2229 Excessive worry 2.4-fold increase in heart attack risk Kubzansky LD et al. Circulation. 1997;95:818-824

Emotion and Heart Health Positive Affect “Feelings that reflect a level of pleasurable engagement with the environment” (environment = everything outside the self) Happiness, joy, excitement, enthusiasm, and contentment 65-99yo with higher positive affect 53% (half) as likely to die in 2 yr study Ostir, GV. J Am Geriatric Soc 2000;48:473–478 660 adults median age 63. Above-average positive affect group lived 7.5 years longer than unhappier half. Levy BR. J Personality and Social Psychology 2002;83:261–270

Emotion and Heart Health Happiness produces… Lower cortisol on working and nonworking days, reduced fibrinogen stress responses, and lower ambulatory heart rate in men. Independent of age, socioeconomic status, smoking, body mass and psychological distress. Steptoe A.Neurobiology of Aging 26S (2005) S108–S112

Theory of Progesterone Steal (aka: Pregnenolone Steal - or - Estrogen Dominance) Adrenal Fatigue assumes an inability to keep up with cortisol production demanded by continued hypothalamic CRH elevation Progesterone (+/-pregnenolone) is “stolen” to make more cortisol Low levels of progesterone out of proportion to estrogen levels = Estrogen Dominance Reinforced by chronic stress causing increased central abdominal fat This fat increases total body estrogen

Theory of Progesterone Steal (aka: Pregnenolone Steal - or - Estrogen Dominance) Complicated perimenopausal anovulation Ovulation leaves behind the corpeus luteum which secretes progesterone for the premenstrual week, “runs out” of progesterone, and triggers menstrual period This theory presumes that fixing adrenal function and estrogen dominance go hand-in-hand I can find no studies (See Case 4) My Clinical experience – progesterone is calming Less insomnia & anxiety, reduction in hot flashes

Theory of Progesterone Steal (aka: Pregnenolone Steal - or - Estrogen Dominance) Progesterone is metabolized in the liver to allopregnanolone which is a GABA receptor agonist Calming Helpful for anxiety, insomnia, hot flashes Topical progesterone bypasses the liver No studies on its effect on GABA receptor My clinical experience – topical progesterone easily adjusted to produce same effects above Is supplemental progesterone effective because of its primary action as a GABA receptor agonist or because it is replacing a deficiency created by chronic stress response by adrenals?

Chronic Stress and Thyroid Hypothalamic CRH neurons project onto hypothalamic Thyrotropin Releasing Hormone (TRH) neurons that govern pituitary’s release of Thyroid Stimulating Hormone (TSH) Chronic stress reduces TRH …lower thyroid fxn Low TSH, normal T4/T3 levels associated with increased mortality in >60yo humans Indicator of chronic stress Adding thyroxine (T4) in borderline hypothyroidism is no better than placebo for cognitive function, mood, or wellbeing Pollock MA et al. BMJ. 2001;323:891-95

Upstream Antecedents Downstream Diagnosis Chronic Stress CRH elevation Cortisol elevation Depression, anxiety, fatigue, IBS, hypothyroid Insomnia, central weight, diabetes, PMS, high BP polycystic ovaries, heart disease

Chinese Medicine and Adrenals

Chinese Medicine and Adrenals Debate: The Root of All Disease boils down to one of two schools of thought Kidney Jing (dependent on KI Yin) Ancestral/genetic inheritance Lifestyle stress, Adrenal Fatigue Enters body at conception Leaves body with last breath Spleen Qi Dependent upon and responsible for proper nutrition, gastrointestinal function, and immune function Three Treasures Jing Qi Shen

Chinese Medicine and Adrenals Adrenals are part of the Kidney Kidney is the solid organ manifesting the Water Element Adrenal Deficiency ~ Water Deficiency Kidney Yin Deficiency Kidney Yang Deficiency Underlying any Yang Deficiency is Kidney Yin Deficiency

Fire Five Elements System of Correspondences Earth Wood Water Metal

Homeostasis Sheng – Ke Cycle Supporting or Augmenting Influence Controlling or Dampening Influence System Self-Correction (in the short term)

Five Element Correspondences Water (Kidney, Bladder) Philosopher, contemplative, remarkably strong or weak motivation/willpower, sensitive to guilt and fear, hurt deeply by abuse, bladder infections, kidney stones, incontinence, joint pain, low back pain, inner chill, music, hearing problems, throat, winter, black, north, salty, cold or heat intolerance Adrenal Gland governed by Water Element Symptoms produced by imbalances in Wood and Fire Elements triggered by Water deficiency

Five Element Correspondences Wood (Liver, Gallbladder) Driven, multiple projects, movement, CEO, anger/anxiety, tight traps/lateral neck/IT band, TMJ, migraine, headaches, caffeine sensitivity, fibromyalgia, blue/green, sour/citrus, Spring, expansion, insomnia (esp. sleep maintenance 11pm-3am), east

Five Element Correspondences Fire (Heart, Small Intestine, Pericardium, Triple Energizer) Creative, CEO, joy, awareness, love/attachment, mania, palpitations, insomnia (esp. sleep initiation), hot flashes, night sweats, cardiac disease, dysrhythmias, red/orange, bitter/roasted, summer, south

Five Element Correspondences Earth (Spleen, Stomach) Nurturing, worry/obsession, GI issues (loose stools, gastritis, bloating, abd pain), sinusitis, cysts, tumors, lumps, dampness, obesity, chronic fatigue (multifactorial), sweet, dampness (cysts, edema), yellow/brown, transitions of seasons, center of compass positions

Five Element Correspondences Metal (Lung, Large Intestine) Respiratory, skin disorders (“3rd lung”), constipation, dryness, sense of duty, grief, loss, depression (multifactorial), flavorful/spicy, white/grey/colorless, autumn, west

Yin & Yang Deficiency & Excess Yin Deficiency Yang will appear in excess with heat, dryness, thirst, back pain, stiffness insomnia, loss of willpower to follow through with action. This is Empty Heat compared to Full Heat (tonify rather than disperse). Yang Deficiency Yin will appear in excess with cold, fluid retention, chills, back pain, daytime fatigue, low libido, loss of willpower to initiate action. This is Empty Cold (tonify rather than disperse). Yang Excess Yang appears in excess with Full Heat – migraines, pressure, bloating, mania, hypertension, anger, insomnia, fever. Full Heat (disperse rather than tonify). Yin Excess Yin appears in excess with Full Cold – usually due to Wind Cold invasion. Stiffness, contraction of tendons, chilliness, severe menstrual or abdominal pain, fluid retention and watery-loose discharges including stools.

The Yo-Yo Rest-Stress Cycle

What to Do? Whip the adrenals to give you more energy Sustained use of hormones (cortisol, pregnenolone, DHEA, thyroid) and other supplements Some brief gain before reaching the cliff’s edge (Bad Idea) Alter your Lifestyle Acknowledge stressors Adequate sleep Appropriate exercise Nutritious diet Moving meditation Psychotherapy Short term supplements

Relaxation Techniques

The Five Agreements by Don Miguel Ruiz 1. Be Impeccable With Your Word.    2. Don't Take Anything Personally.  3. Don't Make Assumptions.  4. Always Do Your Best. 5. Be Skeptical, But Learn to Listen.

Relaxation Techniques Cognitive Behavioral Therapy or other Psychotherapy Moderate Graded Exercise Tai Chi Yoga Meditation Guided Imagery

Cognitive Behavioral Therapy Form of psychotherapy – goal is to identify, modify and change factors that may be maintaining symptoms Individualized therapy to improve patterns Rest, activity, sleep patterns, exercise capacity, cognition, coping strategies, problem solving, reducing stress, anxiety and depression Well studied and effective in Chronic Fatigue Syndrome Meta analysis reviewed 10,768 publications published on interventions for chronic fatigue syndrome and selected 70 that met the selection criteria Cognitive Behavioral Therapy had best evidence of best outcomes Moderate Graded Exercise was 2nd best evidence/outcomes Chambers D et al. J R Soc Med. 2006;99:506-520 Improving fatigue symptoms and cortisol levels Possible exception – very low morning cortisol may predict less response to CBT

Psychotherapy Professional burnout (exhaustion, fatigue, feelings of reduced competence) 14 sessions of psychotherapy Low morning cortisol prior to series of treatments - increased after 14 sessions Mommersteeg PM. Health Psychology. 2006;25(2): 243-248

Exercise Moderate Graded Exercise Exercise with moderate exertion that gradually increases in intensity over 6-8 weeks Avoids over-exertion which causes post-exercise worsening of fatigue condition 148 patients with Chronic Fatigue Syndrome randomized to moderate graded exercise versus standard medical care Highly significant improvements in physical functioning, sleep, fatigue, mood, and disability Powell P et al. BMJ 2001; 322 : 387 Cochrane review of 9 randomized trials Moderate graded exercise effective for fatigue Better than prozac, though prozac plus exercise superior Edmonds M et al. Cochrane Database of Systematic Reviews 2004, Issue 3

Tai Chi Moving Meditation Equivalent to moderate physical exercise (walking 6mph) and superior to sitting meditation and neutral reading in 96 men and women Reducing stress-induced elevations of urine catecholamines (stress hormones), salivary cortisol, pulse, and blood pressure Jin P. J Psychosom Res. 1992;36(4);36-70

Tai Chi After heart attack, Tai Chi more effective than moderate exercise or support group in lowering diastolic BP Channer KS et al. Postgrad Med J 1996; 72: 349-351 66 Tai Chi practitioners controlled for experience and time of day. Pre and post… Serum cortisol, norepinephrine, heart rate, Profile of Mood States, Trait Anxiety Inventory More experienced practitioners had higher pulse rates Slowly learned skill which will result in more benefits with experience Mood improved and remained elevated > 1 hour Reduced tension, anger, fatigue, depression, confusion, anxiety, cortisol, and norepinephrine Tai Chi has low physical workload - 50% of VO2 max Jin P. J Psychosom Res. 1989;33;197-206

Meditation Sitting Meditation effective for relieving stress Improves cortisol, pulse, blood pressure, total protein, reaction time Sudsuang R et al. Physiol Behav. 1991 Sep;50(3):543-8 Compassion meditation vs discussion group Cortisol, IL-6, Profile of Mood States, Trier Social Stress Test measured before and after No group difference Subset who meditated longer than the median had significant improvements in IL-6, POMS, TSST but not cortisol Pace TWW et al. Psychoneuroendocrin 2009;24(1):87-88 Sitting Meditation not as effective as Tai Chi Jin P. J Psychosom Res. 1992;36(4);36-70

Yoga Women in 3-month yoga training versus wait list controls Improved perceived stress, State and Trait Anxiety, well-being, vigor, fatigue, depression, pain relief, salivary cortisol levels Michalsen A et al. Med Sci Monit, 2005; 11(12): CR555-561 Effective in women with breast cancer Fatigue, well-being, sleep, cortisol levels Raghavendra RM J Clin Oncol 28:15s, 2010 (suppl; abstr 9099

Guided Imagery 13 week program of Bonny Guided Imagery and Music Profile of Mood States test Morning cortisol Tests baseline, after 13 wks, & 6 months later Improved mood, depression states, and morning cortisol McKinney CH. Health Psychology. 1997:16(4):390-40

Perspective Moving Meditation Experience Grows Meditation study Tai Chi superior to Sitting Meditation for improving stress response Jin P. J Psychosom Res. 1992;36(4);36-70 I assume a likely similar finding for yoga, but have not seen comparison study. I assume that very active and rhythmic engagement of spine and pelvis is the mechanism for this difference Experience Grows Tai Chi study More experienced practitioners had higher pulse rates Slowly learned skill which will result in more benefits with experience Jin P. J Psychosom Res. 1989;33;197-206 Meditation study Subset who meditated longer than the median had significant improvements in stress response Pace TWW et al. Psychoneuroendocrin 2009;24(1):87-88

A Few Cases

Case 1: Cortisol High, DHEA low 62yo F with fatigue for 5 months and feels cold, sweaty all day. Chronic insomnia. Major stressor: frequent interstate travel to care for father with dementia in setting of lack of support by local sibling and intermittent sibling conflict Low basal body temp 97.3-97.7. Long flu-like illness 1 month earlier complicated her fatigue Acupuncture and (Chinese Herbal) Minor Bupleurum started for 4-6 weeks, labs drawn. TSH 1.56, Free T3 2.9, Free T4 1.37, RT3 30, normal CBC and Chem 7

Case 1: Cortisol High, DHEA low

Adrenocortex Stress Profile (saliva sampling x 4 in one day)

Case 1: Treatment Plan Encourage adequate rest and sleep Meditation training referral Acupuncture Tonify Kidney Yin and settle Heart Shen CorticoB5B6 (Vit C 250mg, B6 100mg, pantothenic acid 500mg, magnesium 75mg, citrus bioflavanoid complex 100mg) 1 tablet three times per day L-Theanine 200mg twice per day GABA 700mg daily in morning DHEA 25mg daily in morning Rescue Formula 3 twice per day (TCM: Heart Shen disturbance)

Case 1: Follow-Up Over the next 3 weeks, GABA increased gradually to 1400mg twice per day and L-theanine increased to 400mg in AM, 200mg in PM Ambien stopped. By week 5-6, Fatigue 75% better, insomnia improving intermittently with no ambien Eventually had to use intermittent lower dose Ambien but able to remain of nightly higher dose

Case 2: Cortisol Low 71yo male with 1 year of worsening profound fatigue. Previously athletic. Now so tired that “the other day I didn’t have the energy to read the newspaper.” Stressors: stressful years in business, divorce, two decades of simple carb diet, prostate cancer 5 years ago, major stress including extensive and prolonged anger 4-5 years ago, low testosterone Other: low back pain, dry mouth, tendency to anger when stressed Exam: horizontal creases in fingerprints, thinning hair and eyebrows, pitted nails, normal heart/lung/abdomen exam.

Case 2: Cortisol Low, DHEA norm

Adrenal Fatigue – Induced Connective Tissue Dysfunction? Creased Fingerprints Suggests deficiency Connective Tissue integrity – often improves with resolution of fatigue Ridged Fingernails Case 2 - Considerably worse than this until 2 months into treatment

Adrenocortex Stress Profile (saliva sampling x 4 in one day)

Case 2: Treatment Plan Acupuncture weekly Kidney Yin, Ming Men tonified (10 treatments over 3 months) Meditation – “too time consuming” Encourage rest when needed and adequate sleep Chinese Medicine (Kidney Yin Deficiency) Nourish the Root 4 tablets at bedtime Gut mucosal and digestive/absorption support: Glutagenics ( L-glutamine 3 grams, DGL 200mg, Aloe 50mg per tsp) 1 teaspoon twice per day Bio-Gest  (Betaine HCl, Ox Bile concentrate, pancreatic enzymes)  2-4 capsules with each meal.  Ultra Flora Plus DF Capsules (Lactobacillus species and Bifidobacteria 15 billion colonies per capsule) 2/day

Case 2: Treatment Plan Adrenal Support: Adreset (1 tablet: cordyceps 400mg, panax ginseng 200mg, rhodiola 50mg) 1 tablet three times per day CorticoB5B6 (1 tablet: Vit C 250mg, B6 100mg, pantothenic acid 500mg, magnesium 75mg, citrus bioflavanoid complex 100mg) 1 tablet three times per day Pregnenolone (1 capsule: 30mg)  1 capsule in morning and afternoon no later than 2pm EPA-DHA 720 (Fish Oil with EPA 430mg, DHA 290mg per gelcap) 2 twice per day Collagen JS (Pure Encapsulations- Hydrolyzed type II collagen complex from chicken sternal cartilege 500mg/capsule) 4 capsules per day with meals and 8oz water Adrenal Rebuilder (porcine adrenal, gonad, hypothalamus and pituitary concentrates processed to remove hormones) 1 pill three times per day for one week and then increase to 2 three times per day on week 2

Case 2: Follow-Up 4 weeks: 85-90% improved compared to 2 years prior. Beginning to exercise 6 weeks: 95% improved. Leg pressed 400lbs 12 repetitions/set for 6 sets at age 72. 3 months: 100% resolved to normal energy. Blood pressure high in 150s for 1st time. Stopped Adreset, Collagen, Pregenonlone, and Biogest 5 months: Blood pressure normal, Fatigue still resolved. Hair and eyebrows thick and bushy after prior thinning. Pitted/ridged fingernails normalized. All supplements stopped. 7 months to 1 year later: Added testosterone in face of history of prostate cancer with close PSA monitoring. Athletic. No fatigue. Vibrant

Risks of Treatment of “Adrenal Fatigue” Expense (short term but significant) High Blood Pressure Resolved by lowering DHEA, pregnenolone, glandular Insomnia DHEA impairs function of Tamoxifen (used in ER positive breast cancer) when level of DHEA-Sulfate > 90 Failure to recognize other causes of fatigue

Case 3: Cortisol & DHEA Normal, Glucose High 38 yo M - fasting glucose 106 with no diabetes risk factors, excellent nutrition, strong family history of early heart disease. Normal blood pressure, BMI 21.5. Tendency to irritability, some fatigue if not rested, back ache, easily chilled, frequent viral infections Stressors: demanding career, family commitments, inadequate sleep due to work and variety of outside interests

Case 3: Cortisol Normal, Glucose High

Adrenocortex Stress Profile

- Case 3 – Cortisol Normal, Glucose High Glucometer for Fasting Blood Glucose over 2 ½ months Best predictor for elevated fasting BG in this case: Inadequate Sleep and 2-3 consecutive work days 4 months, 1 year, 2 years out Glucometer with “lifestyle diary” as Biofeedback

Case 3: Treatment Plan Promote adequate rest, Tai Chi, yoga, meditation, exercise, counseling referral Acupuncture weekly x 5-8 weeks Alternate Liver Qi movement, Kidney Tonification Chinese herbs for Kidney Yang Deficiency Dynamic Warrior 60 drops/day in AM Warmth Keep warm while exercising Eat warming foods (teas, garlic, ginger, steamed vegetables vs. raw) Avoid cold foods (ice, cool liquids, minimize raw veg)

Case 4: Perimenopausal Anovulation 42 yo female, normal BMI 24, exercises, fit Mild autoimmune hypothryoidism 2005 History suggestive of mild Adrenal stress 4/2010 low secretory IgA, salivary cortisol mildly low in AM (rest of day normal). Normal fasting insulin and 17-OH progesterone Secretory IgA low levels strongly correlate with daily stress, loss of sense of humor, negative emotions, anger/irritability Martin RA. Int J Psychiatry Med 1998;18:93-105. Rein G. J Adv Med 1995;8:87-105 Fatigue responsive to adrenal support supplements in Summer 2010, but increased androgenic effect (mild facial hair) - Supplements stopped 9/2010 Fatigue partially returned, then better with change from sustained release T3/T4 to Armour Thyroid (low dose 15mg)

Case 4: Perimenopausal Anovulation Missed menstrual period 9/2010 Self-corrected – menstruation 10/2010 Single ovarian cyst found on ultrasound 10/2010 (not polycystic) Spring 2011 - Missed menstrual period 60+ days Abdominal bloating/discomfort, fatigue, hot flashes Family history of early menopause Question: Is this perimenopause? Is thyroid dose correct? Time for hormones? Which?

Urine Pregnancy Negative Thyroid normal TSH 1.97, FT4 0.93, FT3 2.9 Luteinizing Hormone 55.9 u/L (0.8-15.5) Follicle Stim Horm 30.7 u/L (1.4-9.6) Progesterone 1.5 ng/ml (1.4-16.6) 1.5mcg/L Estradiol 129 pg/ml (19-157) 0.129mcg/L Because FSH is only 30 and is about half LH, this is not menopause yet (would be very high FSH) With Progesterone very low, Estradiol modest, and LH high, this is “anovulation”. Treatment: Progesterone x 7-10 d Ovulation triggered by LH Surge. If this is not high enough or is gradual or poorly timed, then ovulation cannot occur. Can stress play a role?

Hypothalamus - Pituitary – Ovary (Stress and the “LH Surge”) Ovulation requires correct timing and level of Luteinizing Hormone (from pituitary) “LH Surge” Pulsing too late, too slowly, or ill timed – no ovulation No ovulation > no corpus luteum > low progesterone LH Surge requires very specific pulsations of Gonadotropin Releasing Hormone by the hypothalamus Can stress influence LH surge? Could influencing any stress effect help alleviate perimenopausal symptoms?

Stress and Anovulation Administering Corticotropin Releasing Hormone (CRH) inhibits release of Gonadotropin Releasing Hormone (GnRH) at the Hypothalamus Stress causes ineffective pulsation of the “LH Surge” Hypothalamic amenorrhea Stress-induced loss of periods Extensive exercise in young athletes with low body fat High cortisol, High ACTH Consistent with chronic stress response Low LH, FSH, estradiol, allopregnanolone Don’t have periods and don’t have enough estrogen to build lining Much less responsive to CRH given experimentally and already prone to lower CRH due to persistently high cortisol (stress) Meczekalski B et al. European Journal of Endocrinology 2000;142:280–285 East German war refugees low cortisol, high LH compared to normal Bauer M et al. Psychiatry Research 1993;5 I:75435 Stress-induced high cortisol, high ACTH, and high CRH all cause pituitary to release a weak LH surge in sheep, cows Breen KM et al. Endocrinology 148(4):1882–1890 Stoebel DP et al. J Dairy Sci 1982;65:1016-1024

Stress and Perimenopause Can stress influence LH surge? Yes Is it possible to reverse the chronic stress response and normalize cortisol and CRH? Could influencing any stress effect help alleviate perimenopausal symptoms? Probably, and with other positive health benefits Other considerations Luteal phase progesterone supplementation to facilitate menstruation Due to development of facial hair (androgen effect) Adaptogens instead of glandulars, pregnenolone, DHEA **Elevated LH also increases androgen production

Case 4 - Treatment Plan Induce menses with “progesterone withdrawal” (7-10 days progesterone – period 2 days later) Self-examine lifestyle Adequate sleep (use relaxants if needed), negative vs. positive emotions, regular moving meditation (Tai Chi or yoga), B-vitamins, fish oil, magnesium, consider adaptogens, acupuncture Consider hormones (Testing is useful) Test menstrual cycle hormone levels (3 day interval) Likely to benefit from additional bioidentical progesterone Oral if planning to use salivary sampling (topical hormones concentrate in saliva, making followup salivary test useless) Birth control pill would help but not likely necessary Avoid blood clot risk by avoiding estrogens if not indicated

Polycystic Ovary Syndrome Lumpkin M. The Hypothyalamic Pituitary Adrenal Axis. Textbook of Functional Medicine. Ed. Jones D. Institute for Functional Medicine. 2005

Supplements Carrot or Stick? Depends on Use.

Perspective There are very few good human studies on the use of supplements for fatigue/stress There are NO long-term supplement studies in fatigue There are numerous studies on Tai Chi, Yoga, Meditation, Exercise, Psychotherapy, Sleep I prescribe supplements with the intention to use them for 2-6 months Goal: Help restore improved function and less fatigue in order to begin and maintain lifestyle changes that are critical to reversing the HPA axis dysfunction Primarily based on clinical experience, some mechanism research

Chronic Fatigue Syndrome - treatment review -. Chambers D et al Chronic Fatigue Syndrome - treatment review - Chambers D et al. J R Soc Med. 2006;99:506-520 Meta analysis reviewed 10,768 publications published on interventions for chronic fatigue syndrome and selected 70 that met the selection criteria Graded evidence and success of several treatments in order 1.Cognitive Behavioral Therapy 2. Graded exercise program 3. Inosine pranobex 4. Low dose hydrocortisone Others deserving mention DHEA Acetyl-L-carnitine and propionyl-L-carnitine EPA-DHA (fish oil) Magnesium

Supplement Categories Adrenal Adaptogens Nutrients B-vitamins Magnesium EPA-DHA (fish oil) Collagen Relaxants Hormones Glandulars

Adrenal Adaptogens Term coined by Russian Lazarev in 1947 and modified by Brekhman in 1960s 1) Harmless to host 2) Nonspecific, general effect 3) Increases resistance to stressors (physical, chemical or biological) 4) Acts as stabilizer/normalizer Examples Rhodiola, Panax ginseng, american ginseng, ashwaghanda, holy basil

Adaptogens - Rhodiola Slows degradation of serotonin, dopamine, NE Prevent catecholamine release & activity in heart muscle Prevent catecholamine depletion in adrenal Stancheva SL. Med Physiol 1987;40:85-87 Maslova LV et al. Eksp Klin Farmakol 1994;57:61-63 60 subjects with fatigue randomized; rhodiola vs placebo Improved concentration, decreased stress-related fatigue, improved cortisol Olsson EM et al. Planta Med 2009;75:105-112 Anxiety improved in RCT of rhodiola use Bystritsky A et al. J Altern Complement Med 2008;14:175-180 Physicians in residency (sleep deprivation, night duty) Reduced fatigue, improved mental performance Darbinyan V et al. Phyotmedicine 2000;7:365-71

Other Adaptogens Ashwagandha (Ayruvedic Medicine) Animal studies show anti-stress, anti-depressant, anxiolytic, anti-inflammatory, antioxidant, immune function improvement effects No large human studies Does not cause high blood pressure, water retention or insomnia sometimes seen in prolonged high dose ginseng use Holy Basil (Ayruvedic Medicine) Reduces blood glucose in clinical trial of Type 2 Diabetics Animal studies: Stabilizes response to stress, immune modulation, liver protective, reduces stomach ulcers

Other Adaptogens Ginseng (Panax, American, Siberian) (Chinese Med) Animal research suggests that the ginsengs produce stress modulation effects opposite the current cortisol status Low cortisol – HPA-axis stimulation High cortisol – HPA-axis relaxation I recommend Panax or American but not Siberian (too excitatory/warm) Gaffney BT et al. Life Sci 2001;70:431-442 Cordyceps (Chinese Medicine) Extensively used in Chinese Medicine for fatigue/vitality, immune dysfunction, and asthma or other causes of lung dysfunction

Nutrients: Adrenal, CNS and GI B vitamins and Magnesium Important co-factors for many reactions in synthesis of neurotransmitters. Well documented calming qualities. EPA-DHA (fish oil) Reduces inflammation, depression, improves lean muscle mass, lowers epinephrine and norepinephrine release in stress response, lower all-cause mortality Chromium – insulin sensitivity, depression, lipids Collagen – chicken sternum – for poor connective tissue in setting of fatigue GI – probiotics, glutagenics

B-vitamins B1 – Riboflavin B3 – Niacinamide Reduces post-operative stress response 120mg injected daily for several days pre-surgery reduced cortisol spike during and immediately following surgery Continued use for days prevented usual post-operative rebound cortisol drop Vinowgradov VV et al. Probl Endokrinol 1981;27:11-16 B3 – Niacinamide High dose (used for lipid treatment) increases REM sleep in normal sleepers, and helpful for insomnia Mechanism: Tryptophan levels likely increased Negative feedback on tryptophan pyrrolase (trypt > niacin) Pushes tryptophan into making 5HTP and then to serotonin Vitamin B6 is important co-factor Robinson CR et al. Biol Psyhiatry 1977;12:139-43

B-vitamins B5 Pantothenic Acid Enhances function of adrenal cortex Also down-regulates adrenal response in times of high stress Blunts response to infused ACTH Adrenal response to Vit B5 depends on current adrenal function B6 Pyridoxal-5-Phosphate (P5P – active form of Vit B6) Essential cofactor for synthesis of serotonin, dopamine and GABA Conversion of tryptophan to 5HTP is the “rate-limiting step for the creation of serotonin Inhibited by stress, P5P deficiency, insulin resistance, Mag def B12 Methylcobalamin Combines with bright light exposure to reset circadian cortisol rhythm (up in AM, low in PM) Folate Required for synthesis of BH4 (tetrahydrobiopterin) which is essential for creation of serotonin, dopamine, epi, & NE

Relaxants L-Theanine (Green Tea is common source – blunts caffeine effect) Increases serotonin, dopamine, glycine Increases alpha-wave activity in brain Calming, more alert, lower pulse rate with stressors Yokogoshi H. Neurochem Res 1998;23:667-73. Yamada T. Amino Acids 2009;36:21-37 Ito K. Nippon Nogeikagaku Kaishi 1998;72:153-7 Kimura K. Biol Psychol 2007;74:39-45 GABA – gamma-Aminobutyric acid – inhibitory neurotransmitter GABA receptor bound by benzodiazepines and sleep aids (calming effect) Reduces stress response, anxiety/panic, insomnia Abdou AM Biofactors 2006;26:201-8 Green ML Biofeedback Self Regul 1988;13:187-99

Relaxants L-tryptophan / 5-HTP (5-hydroxytryptophan) Precursor to serotonin. As effective as tricyclics for depression. Improves Premenstrual mood swings. Improves sleep onset and quality. Richard DM. Int J Tryptophan Res. 2009 March 23; 2: 45–60 Does not limit cognitive performance or inhibit arousal from sleep Lieberman HR. Am J Clin Nutr 1985;42:366-70 5HTP 2mg/kg effective for childhood night terrors Bruni O et al. Eur J Pediatr 2004;163:402-7 Bacopa (Ayruvedic Medicine) Effective for anxiety and cognitive function in randomized trials Singh RH et al. J Res Ayru Siddha1980;1:133-148 Stough C. Psychopharmacology 2001;156:481-84 Calabrese C. Altern Complement Med 2008;14:707-13

Relaxants L-Tyrosine Melatonin Precursor to catecholamines (dopamine, epinephrine, norepinephrine) Helps prevent stress-induced depletion of catecholamines Improved performance in stressful situations Melatonin Well documented efficacy for insomnia and jet lag Can cause dream disturbed sleep Can inhibit arousal from sleep (sleep hangover effect)

Hormones A word to the wise…. Use as little dose (per day and over time) as necessary Avoid very long periods (>6 months) if possible Accept the risks if outweighed by benefits Try intermittent downward tapers of hormones If low hormones are replaced, the rest of the Endocrine System will respond/adjust Very complex system Screen for prostate/breast cancer Remember the Carrot/Whip metaphor

Glandular Hormones Animal endocrine organs purified/extracted/dried Common example of standardized glandular is Armour Thyroid Literature review dominated by 1930-1940s – no current scientific articles on medicinal use of adrenal glandular Adrenal cortical extract Injected into children, studied blood chemistry and immunological effects Increased cholesterol, tendency toward lower glucose level. Normal CBC, sedimentation rate, total protein and pertussis titres – no change Kelley VC, Adams JM. J Peds 1948;32(3):282-287 My anecdotal clinical experience Equivalent to a low dose of cortisol, frequently helpful for fatigue Adverse: Can cause over-stimulation of the HPA Axis – increased cortisol, insomnia, high blood pressure, “wired” effect Two concerns: 1) prolonged use (>6 months) 2) contaminants from food chain

Hormones Pregnenolone Progesterone – previously discussed Modulates NMDA and GABA receptors Use – in setting of low cortisol with fatigue Short term 2-3 months for symptomatic relief. Increase exercise, rest, relaxation, adaptogens Adverse – increased androgens (hair growth, acne, irritability), insomnia, palpitations Progesterone – previously discussed No long-term studies

Hormones - DHEA Effective in major and non-major depression in men and women Wolkowitz OM et al. Am J Psychiatry.1999;156:646-649 Rabkin JG. Am J Psychiatry. 1996;163:59-66 Schmidt. Arch Gen Psychiatry. 2005;62:154-162 Improves concentration, libido and fatigue in small studies of Chronic Fatigue Syndrome and Lupus Adverse effects Facial hair, acne, irritability, elevated BP, insomnia, reduces efficacy of tamoxifen if DHEA-S levels >90 Theoretical fear of amplifying breast/ovarian/prostate cancer due to conversion to estrogen and testosterone – clinical exam and lab screening No long term studies to establish safety of long term use

Hormones - Cortisol 5-10mg/day for 1 month effective for CFS without psychological diagnosis Physiologic dosing equivalent Reduced fatigue without affecting endogenous adrenal function Cleare AJ et al. Lancet 1999; 353(9151):455 – 458 Well established in Adrenal Insufficiency Failure to double cortisol level with ACTH 250mcg No long-term studies other than Adren Insuff

Supplements I select supplements based either on testing or on questionnaire-based protocol Adrenocortex Stress Profile Salivary Cortisol at 7AM, 10AM, 4PM, 11PM Salivary DHEA at 7AM Some tests include 17-OH Progesterone More objective rationale for use of progesterone, however clinical observation is as useful Thyroid studies, CBC, Chem 14 Make sure no thyroid, hematologic, kidney, liver dz Metagenics Stress IdentiT protocol

Summary Chronic, persistent stress is harmful & feels bad Restful, uninterrupted sleep is essential Loosen Attachment to Destructive Emotions Anger, worry, anxiety, irritability Psychological counseling important Promote positive outlook Tai Chi, Yoga, Moderate Exercise, Meditation Supplements can play a role for short term 2-6 months Not likely good to use on a chronic, continuous basis Used to improve quality of life and well-being long enough to take advantage of lifestyle changes

The Five Agreements by Don Miguel Ruiz 1. Be Impeccable With Your Word.    2. Don't Take Anything Personally.  3. Don't Make Assumptions.  4. Always Do Your Best. 5. Be Skeptical, But Learn to Listen.

Stress, Fatigue and The Adrenals www.drtomsalchemy.com Stress, Fatigue and The Adrenals Tom Archie, MD St Luke’s Wood River Family Medicine