10/7/2019 HPA-Stress-Cortisol: Connecting the Dots Carrie Jones ND, MHP 1 The HPA Axis 2 Reminder: • Not everything is absolute regardless of the literature • Not all patients test, react or respond like we expect • The lists in these lectures are not necessarily exhaustive • References are provided – please read them for more info! • Utilize your supplement reps/compounding pharmacists! • Remember those pillars of health • Lastly… 3 1 10/7/2019 4 HPA Axis Physiology Recap 5 Nervous System Central Peripheral (brain & spinal cord) A reminder of where we are focusing: Somatic Autonomic (Voluntary skeletal (self-regulated actions of movements and sensory) organs/glands) Enteric (intrinsic) Parasympathetic Sympathetic 6 2 10/7/2019 What is the HPA Axis? Hypothalamus Pituitary Adrenal 7 Anatomy, Physiology and Metabolism 8 Zoom in on the adrenal gland 9 3 10/7/2019 Zoom in on the adrenal gland 10 Let’s first focus on cortisol 11 How is cortisol made? Some hormones are made from circulating precursors, but cortisol production is not made this way It’s not made from circulating pregnenolone or progesterone 12 4 10/7/2019 First step: Steroid Biochemistry Star Is cortisol made from pregnenolone or progesterone? 13 Cholesterol’s cleavage to pregnenolone by cholesterol desmolase is the rate limiting step in cortisol production (Adrenocortical cells contain large stores of lipids for steroidogenesis) Anitescu M, Benzon H and Variakojis R. (2014). Practical Management of Pain (5th Edition) Chapter 44 – Pharmacology for the Interventional Pain Physician. Amsterdam, Netherlands. Elselvier. 14 15 5 10/7/2019 16 Adrenal Cortex Cell Mitochondria 17 18 6 10/7/2019 Cortisol Production • About 70% of the adrenal cortex is the zona fasciculata cortisol production! • <5% of cortisol is circulating as free • Bound primarily to cortisol binding globulin (90%) and albumin (10%) • Cortisone also circulates and binds to CBG Anitescu M, Benzon H and Variakojis R. (2014). Practical Management of Pain (5th Edition) Chapter 44 – Pharmacology for the Interventional Pain Physician. Amsterdam, Netherlands. Elselvier. 19 Cortisol Production Made primarily by the adrenal gland in a diurnal pattern SALIVARY DIURNAL FREE CORTISOL PATTERN URINE FREE CORTISOL PATTERN 20 What is considered a “normal” response? 21 7 10/7/2019 What is considered a “normal” response? 22 What is considered a “normal” response? 23 What is considered a “normal” response? 24 8 10/7/2019 What is considered a “normal” response? 25 Why is this important? “The circadian rhythm regulation plays a crucial role in people’s healthy lives affected by factors consisting of cosmic events related to the universe and earth, environmental factors (light, night and day duration, seasons) and lifestyles.” “These factors changes lead to disturbance of circadian rhythm, and it causes increasing the incidence of mental diseases like depression and physiological problems like cancers, cardiovascular disease and diabetes.” Farhud D and Aryan Z. Circadian Rhythm, Lifestyle and Health: A Narrative Review. Iran J Public Health. 2018; 47(8): 1068–1076. 26 (Farhud & Aryan, 2018) 27 9 10/7/2019 Cortisol’s Physiologic Effects • Metabolism: • Hemodynamic: • Degrades muscle protein and • Maintains vascular integrity and increases nitrogen excretion reactivity • Increases gluconeogenesis and • Maintains responsiveness to plasma glucose levels catecholamine pressor effects • Increases hepatic glycogen • Maintains fluid volume synthesis • Central Nervous System: • Decreases glucose utilization • Modulates perception and • Decreases amino acid emotion utilization • Decreases CRH and ACTH • Increases and redistributes fat release 28 Cortisol’s Physiologic Effects • Immune Function: • Increases anti-inflammatory cytokine production • Decreases pro-inflammatory cytokine production • Decreases inflammation by inhibiting prostaglandins and leukotriene production • Inhibits bradykinin and serotonin inflammatory effects • Decreases circulating eosinophil, basophil, and lymphocyte counts • Increases neutrophil, platelet, and RBC counts • Impairs cell mediated immunity • Support glucocorticoid induced thymocyte apoptosis for T-cells who fail central tolerance 29 Now that you’ve made it.. Where does it go? 30 10 10/7/2019 Cortisol Metabolism Tetrahydrocortisol (THF) Tetrahydrocortisone (THE) 31 Activation to Cortisol Deactivation to Cortisone • Liver • Kidneys • Adipose • Colon • Gonads • Salivary gland • Brain • Vascular smooth muscle Liver Metabolism (irreversible) 32 Quick recap: you now understand… • This is the HPA axis • How cortisol is made (and not made) • What it does (physiologic effects) • There is a diurnal pattern • Cortisol and cortisone go back and forth via 11b-HSD • Cortisol and cortisone get metabolized in the liver • The metabolites end up in urine How do you test all of this? 33 11 10/7/2019 Directly Related Lab Measurements • Free cortisol (active) • Free cortisone (inactive) • Cortisol metabolites • a-THF, b-THF (tetrahydrocortisol) • b-THE (tetrahydrocortisone) • Most of the cortisol you make ends up excreted as one of these metabolites 34 What can labs tell us about cortisol? Diurnal pattern of cortisol production • Saliva or urine free cortisol Stress response resiliency • Saliva (Cortisol Awakening Response) Total production of cortisol • Urine cortisol metabolites total (THF+THE) Metabolic preference cortisol vs cortisone • Urine 11b-HSD1 vs 11b-HSD2 35 Cortisol Disease States: • Addison’s Disease = autoimmune disease of the adrenal glands resulting in too little production of cortisol and aldosterone 36 12 10/7/2019 Addison’s Disease (saliva/urine combo) Saliva free Urine metabolites cortisol near zero near zero Pattern is a low flat line 37 Addison’s Disease (urine only) Urine free Urine metabolites cortisol near zero near zero Pattern is a low flat line 38 Cortisol Disease States: • Addison’s disease = autoimmune disease of the adrenal glands resulting in too little production of cortisol and aldosterone • Cushing’s Syndrome = excessive amounts of cortisol in the body regardless of the cause • Commonly due to steroid use • Cushing’s Disease = excessive cortisol due to a tumor 39 13 10/7/2019 Cushing’s Disease (saliva/urine combo) Saliva free cortisol Urine metabolites Elevated pattern not following VERY high confirm elevation a circadian rhythm 40 The focus of Functional Endocrinology goes beyond disease states! 41 Functional Endocrinology Identify disease states (Cushing’s/Addison’s) “Generalized HPA axis dysfunction” is what more commonly occurs and must be addressed 42 14 10/7/2019 Functional Endocrinology 43 Functional Endocrinology 44 Acute Stress Chronic Stress 45 15 10/7/2019 Acute Stress Chronic Stress 46 Acute Stress Chronic Stress 47 Acute Stress Chronic Stress 48 16 10/7/2019 HPA Axis Dysfunction – High or Low Cortisol • An “acute stressor” leading to increased cortisol is an appropriate response that is short-lived = optimal HPA axis function • When the stressor persists or with multiple stressors a chronically high cortisol state becomes the new norm = adaptive to chronic high cortisol state • Long term, chronic stress can lead to HPA axis down-regulation (decreased receptor sensitivity) and a low cortisol state • There are conditions where CRH secretion is chronically reduced = adaptive to chronic low cortisol state 49 What is “Adaptive Cortisol?” • Describes HPA axis dysfunction that is not distinctly “high cortisol” or “low cortisol” • In the stages of stress, “Adaptive” may precede a high or low cortisol state as HPA dysfunction progresses 50 Citations • Chrousos GP and Gold PW. JAMA. 1992; 267(9): 1244: 1252 • Chrousos GP. Hypothalamic –pituitary-adrenal axis and immune mediated inflammation. N Engl J Med. 1995; 332(20): 1351- 1362 • Tsigos C and Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002; 53(4): 865-871 • Hoshiro M, et al. Clin Endocrinol. 2006; 64(1): 37-45 51 17 10/7/2019 Citations • Guilliams T. (2015). The Role of Stress and the HPA Axis in Chronic Disease and Management. Stevens Point, WI: Point Institute • Hall JE (2016). Guyton and Hall Textbook of Medical Physiology 13th Edition. Philadelphia, PA: Elsevier • McEwen BS. Neurobiological and systemic effects of chronic stress. Chronic Stress (Thousand Oaks). 2017; 1: 1-18 • Molina PE (2018). Endocrine Physiology 5th Edition. New York, NY: McGraw Hill 52 Brief Overview: High Cortisol Comorbidities 53 Potential High Cortisol Causes: • Cortisol supplementation • Stress (physical, mental, chemical) • Acute inflammation • Acute pain • Acute infection (stealth or overt) • Blood sugar/insulin dysregulation • Caffeine/stimulant use • Poor sleep hygiene • Hyperthyroidism • Cushing’s syndrome or disease 54 18 10/7/2019 High Cortisol Signs and Symptoms • Mood • Vasomotor symptoms • Irritability, anxiety, panic attacks • Hot flashes, night sweats • Sadness, depression • Metabolism • Sleep Disturbances • Central weight gain • Can’t fall asleep, can’t stay asleep • Carbohydrate cravings • Energy • Glucose/insulin dysregulation • Fatigue, wired and tired • Hair loss • Pain • CNS • Brain fog, memory • Increased Blood Pressure • Immunity • GI • Increased infections • Constipation, diarrhea 55 Common Comorbidities of High Cortisol • Melancholic depression • GI • Ovulatory issues • Impaired memory 56 Melancholic Depression • Pronounced alterations in the HPA axis with dysphoric hyperarousal and relative immunosuppression • Innate and T-helper 1 (TH1) cell directed immunosuppression