Stress, Fatigue and The Adrenals

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

2. When My Patients Visualize Stress…

3. When I Visualize Stress

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

5. 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

6. 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

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

8. 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

9. 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 

10. 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

11. Mayo Clinic on “Adrenal Fatigue”www.mayoclinic.comMay 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

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

13. Functional Medicine Matrixwww.functionalmedicine.org

14. 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.

15. 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

16. Perceived Stress • Origin • 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

17. 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

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

19. 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

20. 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

21. 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

22. Event Data mixes withEmotional 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.

23. 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

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

25. 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”

26. 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

29. 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

30. 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

31. 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

32. Chronic StressProlonged 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.

33. 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

34. 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

35. 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

36. 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

37. 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

38. Adrenal Fatigue Observationson 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

39. 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

40. 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

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

42. 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

43. 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

44. 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

45. 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

47. 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

48. 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

49. 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?

50. 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