The HPA Axis

10/7/2019

HPA-Stress-Cortisol: Connecting the Dots

Carrie Jones ND, MHP

The HPA Axis

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…

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HPA Axis Physiology Recap

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

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What is the HPA Axis? Hypothalamus Pituitary Adrenal

Anatomy, Physiology and Metabolism

Zoom in on the adrenal gland

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Zoom in on the adrenal gland

Let’s first focus on cortisol

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

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First step: Steroid Biochemistry

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Is cortisol made from pregnenolone or progesterone?

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

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Adrenal Cortex Cell

Mitochondria

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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

What is considered a “normal” response?

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What is considered a “normal” response?

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What is considered a “normal” response?

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

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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

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

Now that you’ve made it.. Where does it go?

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Cortisol Metabolism

Tetrahydrocortisol (THF) Tetrahydrocortisone (THE)

Activation to Cortisol Deactivation to Cortisone • Liver • Kidneys • Adipose • Colon • Gonads • Salivary gland • Brain • Vascular smooth muscle

Liver Metabolism (irreversible)

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?

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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

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

Cortisol Disease States: • Addison’s Disease = autoimmune disease of the adrenal glands resulting in too little production of cortisol and aldosterone

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Addison’s Disease (saliva/urine combo)

Saliva free Urine metabolites cortisol near zero near zero

Pattern is a low flat line

Addison’s Disease (urine only)

Urine free Urine metabolites cortisol near zero near zero

Pattern is a low flat line

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

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Cushing’s Disease (saliva/urine combo)

Saliva free cortisol Urine metabolites Elevated pattern not following VERY high confirm elevation a circadian rhythm

The focus of Functional Endocrinology goes beyond disease states!

Functional Endocrinology

Identify disease states (Cushing’s/Addison’s)

“Generalized HPA axis dysfunction” is what more commonly occurs and must be addressed

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Functional Endocrinology

Acute Stress  Chronic Stress

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Acute Stress  Chronic Stress

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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

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

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

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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

Brief Overview: High Cortisol Comorbidities

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

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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

Common Comorbidities of High Cortisol

• Melancholic depression • GI • Ovulatory issues • Impaired memory

Melancholic Depression • Pronounced alterations in the HPA axis with dysphoric hyperarousal and relative immunosuppression • Innate and T-helper 1 (TH1) cell directed immunosuppression • Increase in certain infections and cancer • Signs and Symptoms include: • Anhedonia, anxiety, insomnia, loss of appetite, depression worse in AM • HPA axis hyperactivity can lead to GR desensitization and an inability to return to basal resting conditions • Systemic sequalae include osteoporosis, Met-S, CAD • Decreased BDNF is linked with depression

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Excess cortisol, estradiol, inflammation and LPS

NAD

Foster J, Rinaman L and Cryan J. Stress & the gut-brain axis: Regulation by the microbiome. Neurobiol Stress. 2017;7:124-136.

Melancholic Depression

• If not treated, decreased life expectancy • SSRI’s blunt HPA axis response • Induce GR downregulation, ↑BDNF • Decrease peak and total cortisol, improving anxiety symptoms • Treatment resistance can occur in 20-30% of MDD patients • Patient’s with treatment resistance have decreased GR function and continued hyperarousal

BDNF (brain derived neurotrophic factor) • Important for neuronal survival and development • Protects against glutamate toxicity • Big player in synaptic plasticity and neurotransmitter release • Heavily concentrated in hippocampus (learning, long term memory) • Also made by platelets, T-cells, monocytes/macrophages • Downregulated by hypercortisolism • Downregulation linked with: • Depression (esp. depression associated with hypercortisolism) • Alzheimer’s and other neurodegenerative disorders • PTSD • Epilepsy

• Sangiovanni E, Brivio P, Dell’Agli M, Calabrese F. Botanicals as Modulators of Neuroplasticity: Focus on BDNF. Neural Plast. 2017;2017:5965371. • Arnason B (ed). (2010). NeuroImmune Biology (Chapter 21- Multiple Sclerosis and Depression: A Neuroimmunological Perspective. Amsterdam, Netherlands. Elsevier. 60

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Melancholic Depression • If not treated, decreased life expectancy • SSRI’s blunt HPA axis response • Induce GR downregulation • Decrease peak and total cortisol, improving anxiety symptoms • Treatment resistance can occur in 20-30% of MDD patients • Patient’s with treatment resistance have decreased GR function and continued hyperarousal

Could you also consider treating this from a functional model? Address the cortisol and support the gut/brain?

Common Comorbidities of High Cortisol • Melancholic depression • GI • Ovulatory issues • Impaired memory

Gut • Dysbiosis: • Cortisol influences intestinal permeability and the gut microbiome’s composition • High cortisol leads to increased intestinal permeability with subsequent increased circulating immunomodulatory cell wall components such as LPS and inflammatory cytokines • Elevated cortisol contributes to the chronic low-grade inflammation seen in patients with significant dysbiosis – as in IBS • IBS: • Data is mixed, most support increased HPA axis activity • HPA axis dysfunction central to IBS etiology

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Common Comorbidities of High Cortisol

• Melancholic depression • GI • Ovulatory issues • Impaired memory

Ovulatory Issues

• Functional Hypothalamic Amenorrhea (FHA) • Low GnRH with low ovarian hormones associated with ↑cortisol • Too few GnRH pulses to drive sufficient FSH and LH release Survival over reproductive activities • Target tissues resistant to hormones

Ovulatory Issues

• Spectrum of hypothalamic-pituitary-ovarian issues: • Luteal insufficiency to complete anovulation and amenorrhea, exercise amenorrhea when observed in athletes, etc

• PCOS and other hyperandrogenic states are also associated with high cortisol state

Resolution of high cortisol can lead to

spontaneous recovery of ovulation

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Cortisol’s Impact on Female Progesterone

• Chronic high cortisol suppresses ovulation

Ovulatory Cycle Anovulatory Cycle

Cortisol is not “stealing” Progesterone

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How does cortisol Glucocorticoids affect hormones like progesterone?

GnRH • Glucocorticoids - can inhibit GnRH

pulses LH/FSH • This results in less - LH and FSH Ovaries stimulation E2/Pg

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How does cortisol Glucocorticoids affect hormones like progesterone?

GnRH • Glucocorticoids - can inhibit GnRH

pulses LH/FSH • This results in less LH and FSH Ovaries stimulation E2/Pg

Common Comorbidities of High Cortisol

• Melancholic depression • GI • Ovulatory issues • Impaired memory

Impaired Memory • Cortisol easily crosses the BBB  binds to hippocampal, amygdala, and frontal lobe receptors influencing learning and memory

• High concentrations of cortisol have been observed in individuals with hippocampal atrophy and cognitive decline • Cortisol the cause or a consequence?

• Long-term exposure to increased endogenous cortisol • Is associated with memory impairment • With aging is associated with smaller hippocampal volume, death of hippocampal neurons and cognitive decline

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High Cortisol Citations

• Tsigos C and Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002; 53(4): 865-871 • Lupien SJ, et al. The Douglas Hospital Long Study of Normal and Pathological Aging: summary of findings. J Psychiatry Neurosci. 2005; 30(5): 328-334 • Lee BH and Kim YK. The Roles of BDNF in the Pathophysiology of Major Depression and in Antidepressant Treatment. Psychiatry Investig. 2010;7(4);231-235. • Ehlert U, et al. High and low unstimulated salivary cortisol levels correspond to different symptoms of functional gastrointestinal disorders. J Psychosom Res. 2005; 59(1): 7-10

High Cortisol Citations

• Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol. 2005; 69(1): 113- 132 • Lara VP, et al. High cortisol levels are associated with cognitive impairment no-dementia (CIND) and dementia. Clin Chim Acta. 2013; 423: 18-22 • Stasi C, et al. Neuroendocrine markers and psychological features in patients with irritable bowel syndrome. Int J Colorectal Ds. 2013; 28(9): 1203-1208

High Cortisol Citations

• Fadgyas-Stanculete M, et al. The relationship between irritable bowel syndrome and psychiatric disease: from molecular changes to clinical manifestations. J Mol Psychiatry. 2014; 2(1): 1-7 • Gold PW. The organization of the stress system and its dysregulation in depressive illness. J Mol Psychiatry. 2015; 20(1): 32-47 • Markert C, et al. Endocrine dysregulation in women with irritable bowel syndrome according to Rome II criteria. J Behav Med. 2016; 39(3): 519-526

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High Cortisol Citations

• Videlock EJ. The effects of sex and irritable bowel syndrome on hypothalamic-pituitary-adrenal axis and peripheral glucocorticoid receptor expression. Psychoneuroendocrinology. 2016; 69: 67-76 • McEwen BS. Neurobiological and systemic effects of chronic stress. Chronic Stress (Thousand Oaks). 2017; 1: 1-18 • Mezullo M. et al. Salivary cortisol and cortisone responses to short-term psychological stress challenge in late adolescents and young women with different hyperandrogenic states. Psychoneuroendocrinology. 2018; 131: 67-72

High Cortisol Citations

• Farzi A, et al. Gut microbiota and the neuroendocrine system. Neurotherapeutics. 2018; 15(1): 5-22 • Lim AJR, et al. Phenotypic spectrum of PCOS and their relationship to the circadian biomarkers, melatonin and cortisol. Endocrinol Diabetes Metab. 2019; 2(3): e00047

Brief Overview: Low Cortisol Comorbidities

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Potential Low Cortisol Causes: • Long-term stress/burnout • Sleep dysregulation • Hypothyroidism • Medications (glucocorticosteroids, opioids, Accutane, aspirin) • Chronic pain/infection = downregulation • Pituitary or hypothalamic dysfunction/lesion • Head trauma/TBI affecting pituitary/hypothalamus • Non-classical congenital adrenal hyperplasia • Surgical removal of adrenal gland • Addison’s disease

Low Cortisol Signs and Symptoms

• AM fatigue • Feeling unmotivated • Sleep disruption • Craving salt and spicy foods • May sleep long – put poor • Anorexia, nausea quality • Allergies • Poor concentration, memory loss • Low blood pressure • Stress induced fatigue • Early onset menopause • Post-exercise • Low libido • Paralyzed by fear • Early life stressors

Comorbidities of Low Cortisol

• Workplace burnout • Atypical depression • Chronic fatigue syndrome (CFS) • Fibromyalgia (FM) • Panic Disorder (PD) and PTSD

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Workplace Burnout • The occupational phenomenon ‘workplace burnout’ was added to ICD-10 • Characterized by: • feelings of energy depletion or exhaustion; • increased mental distance from one’s job, or feelings of negativism or cynicism related to one’s job; and • Reduced professional efficacy • Increased risk of: • Anxiety, depression, fatigue and insomnia • Cardiovascular disease (CAD, DM2, hyperlipidemia, HTN) • Suicide/suicidal ideation • Alcohol use (esp in males) • Psychoactive drug use (illicit or legal)

Practitioner Heal Thyself Me trying to excel in my career, maintain a social life, drink enough water, exercise, text everyone back, stay sane, survive and be happy

Comorbidities of Low Cortisol

• Workplace burnout • Atypical depression • Chronic fatigue syndrome (CFS) • Fibromyalgia (FM) • Panic Disorder (PD) and PTSD

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Atypical Depression

• Precise definition is debatable, not so for melancholic depression • Thought to be the antithesis of melancholic depression • Atypical depression characterized by • Feels best in AM, worst symptoms in the PM • Lethargy, fatigue, excessive sleepiness • Increased food intake, weight gain • Sense of disconnectedness and emptiness • “Unhinged” immune system with increased autoimmune risk and a chronic low grade inflammatory state

Atypical Depression • Atypical depression has an earlier onset and is more frequently chronic • Significantly higher incidence of childhood and adolescent adverse life events • Etiology secondary to HPA axis down-regulation and CRH deficiency Adapted from: Gold PW, Chrousos GP. Mol Psychiatry. 2002; 7(3): 254-275

Comorbidities of Low Cortisol

• Workplace burnout • Atypical depression • Chronic fatigue syndrome (CFS) • Fibromyalgia (FM) • Panic Disorder (PD) and PTSD

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Chronic Fatigue Syndrome (CFS) • HPA axis dysregulation may play a key role in CFS • CFS patients have decreased cortisol activity and lower cortisol stress reactivity • Early life stress and early childhood trauma may partially explain the HPA axis dysregulation • Childhood trauma a key risk factors for CFS development • A history of emotional neglect in CFS patients is related to reduced HPA axis reactivity • CFS patients with reduced HPA axis reactivity have worse treatment outcomes – cognitive behavior therapy can increase HPA axis response

Comorbidities of Low Cortisol

• Workplace burnout • Atypical depression • Chronic fatigue syndrome (CFS) • Fibromyalgia (FM) • Panic Disorder (PD) and PTSD

Fibromyalgia (FM)

• FM patients experience chronic pain that may be associated with chronic fatigue, sleep disturbances, and depression • Adverse childhood events has been associated with FM • FM patients have high levels of subjective stress and are in a constant “fight or flight” mode • Studies evaluating FM and HPA axis dysfunction show mixed results – possibly because of the associated symptoms, or during different time periods along the “cortisol spectrum” • Most agree that FM is associated with hypocortisolism • 2015 study, FM patients in response to a stressor, had lower cortisol levels and a blunted cortisol response compared to controls

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Comorbidities of Low Cortisol

• Workplace burnout • Atypical depression • Chronic fatigue syndrome (CFS) • Fibromyalgia (FM) • Panic Disorder (PD) and PTSD

Panic Disorder (PD) and PTSD • PD and PTSD share common symptoms and often co-occur • Panic attacks and avoidance behavior • Existing literature suggests similar diurnal patterns • Data for both is mixed, however, most favor a hypocortisol state • In 2017, Wichmann, et al., compared PD vs PTSD vs controls and found a lower cortisol pattern in PD and PTSD that reached statistical significance • Because there is a paucity of longitudinal study data for both disorders unclear, if initially hyper-responsiveness predicts hypo- responsiveness

PTSD Example: Low Cortisol (CAR)

Control

PTSD

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PTSD example: low cortisol (CAR)

Control

PTSD The lower CAR indicates lower resiliency but the HPA axis still communicates

Comorbidities of Low Cortisol

• Workplace burnout • Atypical depression • Chronic fatigue syndrome (CFS) • Fibromyalgia (FM) • Panic Disorder (PD) and PTSD • Adverse childhood event (ACE)/childhood trauma • Not exactly a comorbidity but important to discuss as it relates to the main comorbidities listed

Example: Childhood Trauma and Cortisol “Compelling evidence suggests that childhood trauma is a major risk factor for the development of mood and anxiety disorders as well as certain medical diseases, including heart disease and disorders such as chronic fatigue and pain syndromes.”

Heim C. Childhood Trauma and Adult Stress Responsiveness. 2009. Retrieved on September 11, 2019 from http://www.child- encyclopedia.com/brain/according-experts/childhood-trauma-and-adult-stress-responsiveness 96

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Childhood trauma has been associated with: • Overexposure of cortisol negatively affects the prefrontal cortex leading to reduced HPA control • Decreased sensitivity to cortisol’s feedback loop in some people but increased sensitivity to the feedback in others • Enhanced immune activation due to HPA dysfunction • This can lead to increased cortisol activating the feedback loop over time • Hippocampal atrophy resulting in a lower CAR • Heightened vigilance, fear and anxiety

1. Heim C. Childhood Trauma and Adult Stress Responsiveness. 2009. Retrieved on September 11, 2019 from http://www.child-encyclopedia.com/brain/according-experts/childhood-trauma-and-adult-stress-responsiveness 2. Suzuki A, Poon L, Papadopoulus AS, Kumari V and Cleare AJ. Long term effects of childhood trauma on cortisol stress reactivity in adulthood and relationship to the occurrence of depression. Psychoneuroendocrinology. 2014 Dec;50:289-99. doi: 10.1016/j.psyneuen.2014.09.007. Epub 2014 Sep 17

Implications of a Flat Diurnal Cortisol Slope

Flattened Diurnal Cortisol Slope: Breast Cancer (BC) • Cortisol dysregulation 20 to chronic/cumulative stress is associated with increased BC incidence and a poorer prognosis • In metastatic breast cancer patients, a flatter cortisol slope predicted shorter survival times • Flatter slope = higher PM cortisol • Flatter slope = loss of diurnal pattern • It is a long-term prognostic indicator

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Flattened Diurnal Cortisol Slope: Whitehall II Study • Cardiovascular Disease • Flatter slopes associated with increased all-cause mortality • Primarily due to increased cardiovascular mortality • Type II diabetes patients • Had a flatter daily cortisol slope than those without diabetes • Those with flatter slopes and raised evening cortisol levels had a higher likelihood of developing diabetes in the future • Obesity • Associated with flatter cortisol curves • A result of lower AM cortisol and higher PM cortisol

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Citations • Oosterholt BG, et al. Burnout and cortisol: Evidence of a lower cortisol awakening response in both clinical and non-clinical burnout. J Psychosom Res. 2015; 78: 445-451. • World Health Organization. International Class of Diseases 2019. Retrieved from: http//www.who.int/mental_health/evidence/burnout/en. • Balayssac D, Pereira B, Virot J, et al. Burnout, associated comorbidities and coping strategies in French community pharmacies—BOP study: A nationwide cross-sectional study. PLoS One. 2017: https://doi.org/10.1371/journal.pone.0182956 • Toker S, Melamed S, Berliner S, Zeltser D and Shapira I. Burnout and risk of coronary heart disease: a prospective study of 8838 employees. Psychosom Med. 2012;74(8):840-847. • Melamed S, Kushnir T and Shirom A. Burnout and Risk Factors for Cardiovascular Diseases. Behavioral Medicine. 1992;18(2):53-60. • Sephton S, et al. Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival. J Nat’l Cancer Inst. 2000; 92(12): 994-1000 • Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002; 53(4): 865-871 • Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry. 2002; 7(3): 254-275

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Citations

• Kumari M, et al. Association of Diurnal Patterns in Salivary Cortisol with All-Cause and Cardiovascular Mortality: Findings from the Whitehall II study. J Clin Endocrinol Metab. 2011; 96(5): 1479-1485 • Wahbeh H, Oken BS. Salivary Cortisol Lower in Post Traumatic Stress Disorder. J Trauma Stress. 2013; 26(2): 241-248 • Gold PW. The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry. 2015;20(1): 32-47

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Citations • Hsiao FH, et al. Habitual sleep-wake behaviors and lifestyle as predictors of diurnal cortisol patterns in young breast cancer survivors: a longitudinal study. Psychoneuroendocrinology. 2015; 53: 60-68 • Kempke S, et al. Effects of early childhood trauma on hypothalamic- pituitary-adrenal axis function in patients with Chronic Fatigue Syndrome. Psychoneuroendocrinology. 2015; 52: 14-21 • Varinen A, Kosunen E, Mattila K, Koskela T and Sumanen M. The relationship between childhood adversities and fibromyalgia in the general population. J Psychosom Res. 2017;99:137-142. • Adam EK, et al. Diurnal Cortisol Slopes and Mental and Physical Health Outcomes: A systematic review and Meta-analysis. Psychoneuroendocrinology. 2017; 83: 25-41

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Citations

• Wichmann S, et al. Cortisol stress response in post-traumatic stress disorder, panic disorder, and major depressive disorder patients. Psychoneuroendocrinology. 2017; 83: 135-141 • Coppens E, et al. Cortisol and Subjective Stress Response to Acute Psychological Stress in Fibromyalgia Patients. Psychosom Med. 2018; 80(3): 317-326 • Juruena MF, et al. Atypical depression and non-atypical depression: Is HPA axis function a biomarker? A systematic review. J Affect Disord. 2018; 233: 45-67 • Yehuda R, Hoge CW, McFarlane AC, et al. Post-traumatic stress disorder. Nat Rev Dis Primers. 2015;8(1):15057. doi: 10.1038/nrdp.2015.57.

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What is the goal of lab assessment? First, rule out disease states

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What is the goal of lab assessment?

First, rule out disease states Then, define the patient along this theoretical spectrum

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How do we test the HPA axis?

And what markers can we measure?

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HPA Axis Testing Options

Saliva Serum Urine

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HPA Axis Testing Options

Saliva Serum Urine

Serum testing of cortisol has limited utility and is not preferred (see preconference lab lecture) You miss: 1. Free cortisol 2. Free cortisol circadian rhythm 3. Cortisol metabolites

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HPA Axis Testing Options

Saliva Urine Either offers information on the HPA axis, and a combination of both gives the most information

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HPA Axis Testing Options

Saliva Urine (dried) 1. Reports Free Cortisol 1. Reports Free Cortisol 2. Reports Circadian Rhythm of Cortisol 2. Reports Circadian Rhythm of Cortisol 3. Reports the CAR 3. Unable to report a true CAR 4. Unable to test Metabolized Cortisol 4. Reports Metabolized Cortisol 5. Reports DHEA or DHEA-S 5. Reports DHEA-S and DHEA Metabolites 6. Reports Melatonin 6. Reports Melatonin 7. Unable to test VMA (Norepi/Epi) 7. Reports VMA (Norepi/Epi)

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HPA Axis Testing Options

Dried Urine + Saliva Combo (DUTCH Plus) 1.Reports Free Cortisol 2.Reports Circadian Rhythm of Cortisol 3.Reports the CAR 4.Reports Metabolized Cortisol 5.Reports DHEA-S and Metabolites 6.Reports Melatonin 7.Reports VMA (Norepi/Epi)

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Cortisol Awakening Response Saliva or urine can be used to assess the diurnal pattern but what is the Cortisol Awakening Response (CAR)?

SALIVARY FREE CORTISOL PATTERN URINE FREE CORTISOL PATTERN

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Cortisol Awakening Response (CAR) • It occurs upon awakening in the absence of any apparent stressful situation or imminent danger • Influenced by “stress anticipation” (which prepares us to deal with the day to come) and our sleep quality the night before • Mediated by an extra-pituitary pathway from the supra-chiasmatic nucleus via hippocampus to the adrenal glands (independent regulation) • Cortisol increases during the second half of the night, but this is separate from the CAR, which results in levels escalating within 60 minutes of waking

Contreras C and Gutierrez-Garcia A. Cortisol Awakening Response: An Ancient Adaptive Feature. Journal of Psychiatry and Psychiatric Disorders 2 (2018): 29-40. 114

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Cortisol Awakening Response

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Cortisol Awakening Response

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Cortisol Awakening Response

Important to know: 1. What is your CAR percent rise/change? 2. What are your actual numbers? 3. Are you in the reference range?

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Why Not Urine for CAR? Why isn’t this the same as a salivary CAR?

URINE FREE CORTISOL PATTERN

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Why Not Urine for CAR? • Why isn’t this the same as a salivary CAR? • The waking sample represents cortisol while you sleep not right at waking like saliva URINE FREE CORTISOL PATTERN

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How does the CAR work?

As awakening gets closer, the pituitary increases ACTH but there is somewhat of a blunting at the adrenal gland

When the eyes open and light enters the SCN  the blunting releases

Cortisol rises sharply = at least a 50% increase in about 30min causing you to move from ‘conscious’ to ‘alert’

Cortisol should then gradually decline

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Retina Hippocampus Light Sensitivity Hippocampal Function Hypothalamus SCN Internal Clock CRH AVP Sympathetic Anterior Nerves Pituitary Negative ACTH feedback inhibition of HPAA

Cortisol Adrenal Cortex

Stalder T, etal. Psychoneuroendocrinology. 2016 Jan;63:414-32. doi: 10.1016/j.psyneuen.2015.10.010. Epub 2015 Oct 20. 121

What does the CAR influence? • Energy levels • Stress response/resilience • Level of feeling “stressed out” • Alertness • Blood sugar management (DM2 risk) • Mood: anxiety, panic, depression, worry • Autoimmune development/progression • Inflammation regulation • Infection regulation • Memory/recall • Cancer outcomes

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Get the CAR Collection Right! A common reason for an abnormal CAR is poor collection • Very early collection (earlier than typical waking) may result in an inflated CAR • Waiting more than 5 minutes after waking results in an erroneously flat CAR (not a true baseline) • Taking longer than 5 minutes to collect flattens the CAR (swab collection is better and used in most studies)

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Get the CAR Collection Right! A common reason for an abnormal CAR is poor collection or collection during an abnormal event

• Very early collection (earlier than typical waking) results in exaggerated CAR If a barking dog wakes you early, your CAR may be higher than normal

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Why Measure Cortisol Awakening Response (CAR)?

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Importance of the CAR

• An independently important marker of HPA axis function • Serves as a “mini stress test” • Reflects the resilience of the stress response

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Benefit of the CAR

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Benefit of the CAR A

The addition of the CAR shows patient B may have more HPA Axis resiliency compared to patient A Patient B is below the reference range but are still B able to get a rise in cortisol

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Ex. You might have an appropriate CAR but you’re below the reference range

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Benefit of the CAR

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A Benefit of the CAR

The addition of the CAR shows patient B may have an exaggerated stress response B

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Sometimes Any Test Will Do!

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Sometimes Any Test Will Do!

Did adding the CAR improve clinical accuracy? Not in this case

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If the CAR is the best, why should we use urine?

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We want those Cortisol Metabolites

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Why is it helpful to know this?

Metabolized cortisol represents 80% of total cortisol production

Free cortisol = 1% (ish) (Stewart and Krozowski, 1999).

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Metabolized cortisol

• Gives us a rough idea of how much cortisol is being made and metabolized in the day IN TOTAL.

• When free and metabolized cortisol align – confirmatory

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Pattern 1: High Free and High Metabolized • Because free cortisol levels are high, the higher levels of metabolites simply confirm the high output of cortisol. • Follow the high cortisol slides

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Pattern 2: Low Free and Low Metabolized • Because free cortisol levels are low, the lower levels of metabolites simply confirm the low output of cortisol. • Follow the low cortisol slides

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Metabolized Cortisol

• Gives us a rough idea of how much cortisol is being made and metabolized in the day IN TOTAL.

• When free and metabolized cortisol align – confirmatory

When free and metabolized cortisol are decidedly different (one is much lower or higher than the other) abnormal cortisol clearance is implied.

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Pattern 3: High Free and Low Metabolized • If metabolite levels are generally lower than free cortisol, the patient may have sluggish cortisol clearance

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Pattern 3: High Free and Low Metabolized

• If metabolite levels are generally lower than free cortisol, the patient may have sluggish cortisol clearance

• This pattern is common in patients with hypothyroidism • Also observed with poor liver function and anorexia

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Pattern 4: Low Free and High Metabolized

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Pattern 4: Low Free and High Metabolized • Even though free cortisol is low, cortisol production is high. • This pattern of rapid cortisol clearance/metabolism is seen in: • Obesity • Hyperthyroidism patients • Possibly with long-term stress • Possibly with chronic fatigue (research is mixed) • Support the HPA axis without stimulating more cortisol production

1. Cleare A. The neuroendocrinology of chronic fatigue. Endocrine Reviews. 2003;24(2):236-252. 2. Jerjes WK, Taylor NF, Peters TJ, et al. Urinary cortisol and cortisol metabolite excretion in chronic fatigue syndrome. Psychosom Med. 2006;68(4):578-582.

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Let’s Focus on Thyroid/Cortisol

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Low Cortisol?

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Low Cortisol?

Prednisone Suppression

Thyroid Overdose • fT3, T4 High • Low TSH

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Low Cortisol?

Prednisone Suppression

If you just focused on the free cortisol, you would miss the bigger picture

Thyroid Overdose • fT3, T4 High • Low TSH

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Thyroid Directly Impacts Cortisol Clearance Cortisol MetabolitesCortisol

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Thyroid Directly Impacts Cortisol Clearance

As someone becomes more hypothyroid, their cortisol metabolism/clearance decreases Cortisol MetabolitesCortisol

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Thyroid Directly Impacts Cortisol Clearance

As someone becomes more hyperthyroid, their cortisol metabolism/clearance increases Cortisol MetabolitesCortisol

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Remember this low cortisol?

Thyroid Overdose • fT3, T4 High • Low TSH

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Correcting Thyroid Overdose

Hyperthyroidism increasing free Thyroid Overdose cortisol clearance • fT3, T4 High • Low TSH

Still have other work to do for their health and HPA Axis Proper Dose of T3/T4 • Diurnal pattern restored

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Thyroid Can Directly Impact Cortisol Metabolism

In these 2 DUTCH patterns, you might want to consider treating the thyroid first with abnormal thyroid serum (but okay to support the HPA at the same time)

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But…does cortisol affect the thyroid? Yes – it’s bi-directional. Pay attention to the DUTCH patterns

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Deiodinases: Enzymes that activate or inactivate thyroid hormones Deiodinase Type 1: • High levels in the liver and kidney • Can increase T4  T3 conversion and degrades rT3 • Can also increase T3 rT3 and degrades T3 Deiodinase Type 2: • High levels in the pituitary, brown adipose tissue (BAT), placenta, heart, skeletal muscle • Converts T4  T3 Deiodinase Type 3: • Located in all tissues except the pituitary • Converts T4  rT3 (inactive)

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• = deactivates T4  rT3 (not T3) (periphery/cellular) • Cortisol can increase D2 in the pituitary • = T4 T3 increases and TSH drops • High cortisol renders target tissues resistant to circulating thyroid hormone

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• In high stress, inflammation, starvation, and oxidative stress (all of which cortisol plays a role) • =decreased concentrations of free and total T3 (due to downregulation of type 1 deiodinase) • CortisolStress can decreaseon the body D1& can increase cause D3 the deiodinase pituitary to look • = deactivates‘normal,’ T4 low rT3 normal (not T3) or(periphery/cellular hyperthyroid) (low TSH) • Cortisol canbut increase the peripheral D2 in the cellspituitary are hypothyroid • = T4 T3 increases and TSH drops • High cortisol renders target tissues resistant to circulating thyroid hormone

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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. Comprehensive study of urinary cortisol metabolites in hyperthyroid and hypothyroid patients. Clin. Endo. 2006; 64, 37-45 • Holtorf K. Peripheral thyroid hormone conversion and its impact on TSH and metabolic activity. J Restorative Medicine. 2014;3:30-52. DOI:10.14200/jrm.2014.3.0103

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What about obesity and cortisol?

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Obesity Directly Impacts Cortisol Clearance

N>5,000 (female) Precision Analytical (unpublished)

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Obesity Directly Impacts Cortisol Clearance

People often assume free cortisol increases with BMI, but it doesn’t

1. Rask, E., et al. “Cortisol Metabolism after Weight Loss: Associations with 11 B-HSD Type 1 and Markers of Obesity in Women.” Clinical Endocrinology, vol. 8, no. 5, 2013, pp. 700-705., doi: 10.1111/j.1365-2265.2012.0433.x 2. Kok, P., Kok, S. W., Buijs, M. M., Westenberg, J. J. M., Roelfsema, F., Frölich, M., … Pijl, H. (2004). Enhanced circadian ACTH release in obese premenopausal women: reversal by short-term acipimox treatment. American Journal of Physiology-Endocrinology and Metabolism, 287(5). doi: 10.1152/ajpendo.00254.2004 3. Abraham, S., Rubino, D., Sinaii, N., Ramsey, S. and Nieman, L. (2013). Cortisol, obesity, and the metabolic syndrome: A cross-sectional study of obese subjects and review of the literature. Obesity, 21(1), pp.E105-E117. 4. Tomlinson, J., Finney, J., Hughes, B., Hughes, S. and Stewart, P. (2008). Reduced Glucocorticoid Production Rate, Decreased 5 -Reductase Activity, and Adipose Tissue Insulin Sensitization After Weight Loss. Diabetes, 57(6), pp.1536-1543. 162

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Obesity Directly Impacts Cortisol Clearance

Instead, as BMI increases, cortisol metabolites increase

N>5,000 (female) Precision Analytical (unpublished)

Obesity Directly Impacts Cortisol Clearance

N>5,000 (female) Precision Analytical (publication pending)

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Obesity Directly Impacts Cortisol Clearance

CAH

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Congenital Adrenal Hyperplasia

21-hydroxylaseX

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Obesity Directly Impacts Cortisol Clearance

CAH

Obese

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The metabolized cortisol helps confirm or further tell a story about your patient’s HPA dysfunction

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Let’s Dive Into Cortisol Results High, low, and adaptive

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Laboratory Assessment • Define the patient along this theoretical spectrum • But how?

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High Cortisol = Excited HPA Axis (Formerly described as phase 1 “adrenal fatigue”)

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What is Defined as “High Cortisol?”

• High free cortisol in more than 1 point or • High for the 5-sample total of free cortisol or • High free cortisol at 1 point with high metabolized cortisol or • Exaggerated CAR (Cortisol Awakening Response) or • Normal free cortisol with elevated free cortisone pattern (rare)

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What is Defined as “High Cortisol?” • High free cortisol in more than 1 point or • High for the 5-sample total of free cortisol or • High free cortisol at 1 point with high metabolized cortisol or • Exaggerated CAR (Cortisol Awakening Response) or • Normal free cortisol with elevated free cortisone pattern (rare)

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“Adaptive” or High Cortisol? Use the metabolized cortisol as a hint – if it’s not high, that one high free point may be situational

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Always Address Potential Root Causes:

• Stress (physical, mental, chemical) • Acute inflammation

Patient reported acute stress and inflammation. Treat root cause first!

Remember high cortisol may be appropriate if stressed

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Treatment Considerations For high cortisol = Excited HPA

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Always Address Potential Cortisol Root 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

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High Cortisol: Lifestyle • Meditation, breathing work, journaling, yoga, Heartmath™, RESPeRATE™

• Vagal nerve exercises

• Increase oxytocin

• Reduce cell phone/EMF exposure

• All can be done throughout the day as needed

Uvnas-Moberg K and Petersson M. [Oxytocin, a mediator of anti-stress, well-being, social interaction, growth and healing]. Z Psychosom Med Psychother. 2005;51(1):57-80. 180

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We all love our cell phones but… rats exposed to 6 hours/day phone in talk mode

Month 1 Month 2 Month 1 Month 2

C = control, no phone SO = shut off but in the cage

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We all love our cell phones but… rats exposed to 6 hours/day phone in talk mode

“Long-term exposure to cell phone RF induces hypertrophy and disorganization of zona fasciculata of the adrenal gland (in rats)”

Month 1 Month 2 Month 1 Month 2

C = control, no phone SO = shut off but in the cage

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What Stimulates the Vagus Nerve?

• End your shower in cold water • Dip your face in cold water • Singing, laughing, chanting, humming LOUDLY • Gargle • Valsalva maneuver • Hold breath and bear down for a few seconds • Meditation • Address your gut • Pre/probiotics, chew your food, enzymes • Yoga • Rhythmic breathing • Lay on your right side

Breit S, et al. Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders. Front. Psychiatry. 2018;9(44):https://doi.org/10.3389/fpsyt.2018.00044 183

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What increases oxytocin?

• Physical touch • Hugging, kissing, cuddling those you love (including pets) • Words of encouragement and appreciation • Genuine laughing – not just LOL • Meditation and prayer • “Eat, drink and be merry” with your friends and family • Breastfeeding

Uvnas-Moberg K and Petersson M. [Oxytocin, a mediator of anti-stress, well-being, social interaction, growth and healing]. Z Psychosom Med Psychother. 2005;51(1):57-80. 184

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The DUTCH Way to Increase Oxytocin

Hank Ginger Jade

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High Cortisol: General HPA Support • A quality multi-vitamin is a good start but consider extra…

• B vitamins • Especially vitamin B5 (500mg) and B6 (P5P specifically: 10-50mg, watch neuropathy) • Vitamin C – 100mg-1000mg/day • Remember dividing it up into smaller doses greatly increases absorption • Acts as an antioxidant in the adrenal gland • Humans don’t make their own vitamin C – see next slide • Magnesium – 250-500mg or Epsom salt baths • Needed for many things but also to make GABA with B6, ↑BDNF • Essential fatty acids – 1000-3000mg/day

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Humans can’t but goats can? ”…goats, for example, produce the vitamin at a striking rate of 200 mg/kg each day.”

https://www.sciencedaily.com/releases/2008/03/080320120726.htm

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Citations:

1.Brody S, Preut R, Schommer K and Schurmeyer TH. A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress. Psychopharmacology. 2002;159(3):319-324. 2.McCabe D, Lisy K, Lockwood C, and Colbeck M. The impact of essential fatty acid, B vitamins, vitamin C, magnesium and zinc supplementation on stress levels in women: a systematic review.2017. JBI Database System Rev Implement Rep. 2017:15(2):402-453. 3.National Institutes of Health. Vitamin C Fact Sheet for Health Practitioners. 2018. Retrieved on September 31, 2019 from https://ods.od.nih.gov/factsheets/VitaminC- HealthProfessional/ 4.Padayatty SJ, Doppman JL, Chang R, et al. Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone. Am J Clin Nutr. 2007;86(1):145-9. 5.Pan L, Jaroenporn S, Yamamoto T, et al. Effects of pantothenic acid supplement on secretion of steroids by the adrenal cortex in female rats. Reprod Med Bio. 2011;11(2):101-104.

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High Cortisol: Calming Support • GABA support • GABA – 250-1000mg/day • Primary inhibitory neurotransmitter in the brain, not thought to cross the BBB, acts via ENS • Pregnenolone – 10-100mg/day • Pregnenolone  ALLO = supports GABA-A receptors • Amino Acids: • L-theanine – 200-600mg/day (drink organic matcha) • Relaxed alertness, often used for anxiety too (inhibits glutamate receptors, ↑BDNF) • 5-HTP – 50mg-300mg/day • Serotonin supportive but be careful if on antidepressant meds) • Tryptophan – 500-1000mg/day • Serotonin supportive but be careful if on antidepressant meds) • (L-taurine) – 250 – 3000mg/day • Calming to CNS as helps K, Na, Mg, Ca in/out of cells

Pinna G, Uzunova V, Matsumoto K, et al. Brain allopregnanolone regulates the potency of the GABAA receptor agonist muscimol. Neuropharm. 2000;30(3):440-448.

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Careful – Don’t Deplete Dopamine

Rate limiting step

http://home.sandiego.edu/~cloer/bio382/382seqanalysis1.html

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High Cortisol: Calming Specific for High 11b-HSD1=THF • Magnolia officinalis – 250-500mg (night) • Want the Honokiol to be >90%, ↑BDNF • Ziziphus vulgaris (Jujube) – 100-500mg/(night) • Specifically for those who can’t sleep through the night • Skullcap (Scutellaria baicalensis) – 250-500mg/(night) • Stronger nervine, anxiolytic • Holy basil (Tulsi/Ocimum sanctum) – 250-1500mg/day or night • Nervine, anxiolytic, okay to use in the day • Green tea (EGCG) – 250-1000mg/day • Polymethoxylated Flavonoids (PMFs) - 150-300mg/day • Nobiletin and tangeretin in oranges are shown to be strongest of flavonoids (often as citrus peel extract)

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Citations: 11b-HSD1:

• Evans M, Sharma P and Guthrie N. (2012). Bioavailability of Citrus Polymethoxylated Flavones and Their Biological Role in Metabolic Syndrome and Hyperlipidemia, Readings in Advanced Pharmacokinetics - Theory, Methods and Applications, Dr. Ayman Noreddin (Ed.), InTech, Available from: http://www.intechopen.com/books/readings-in-advanced-pharmacokinetics- theory-methods-andapplications/the-bioavailability-of-citrus-polymethoxylated-flavones • Diederich S, Grossman C, Hanke B, Quinkler, M, Herrmann M, Bahr V and Oelkers W. In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I. Eur J Endocrinol. 2000;142:200-207. • Hintzpeter J, Stapelfed C and Maser E. Green tea and one of its constintuents, epigallocatechine 3 gallate, are potent inhibitors of human 11b-hydroxysteroid dehydrogenase type 1. PLoS ONE. 2014;9(1):1-9. • Horigome H, Homma M, Hiran T, Oka T, Niitsuma T, and Hayashi T. Magnolol from Magnolia officinalis inhibits 11beta- hydroxysteroid dehydrogenase without increases of corticosterone and thymocyte apoptosis in mice. Planta Med. 2001;67(1):33- 7. • Masato H, Oka K, Niitsuma T, and Itoh H. A novel 11b-Hydroxysteroid dehydrogenase inhibitor contained in Saiboku-To, a herbal remedy for steroid-dependent bronchial asthma. J Pharmacy Pharmacol. 1994;46(4):305-309. • Richard E, Illuri R, Bethapudi B, Anandhakumar S, Bhaskar A, Velusami CC, and Mundkinajeddu D. Anti-stress Activity of Ocimum sanctum: Possible Effects on Hypothalamic–Pituitary–Adrenal Axis. Phytother Res. 2016;30(5):805-14. • Schweizer R, Atanasov A, Frey B, and Odermatt A. A rapid screening assay for inhibitors of 11β-hydroxysteroid dehydrogenases (11β-HSD): flavanone selectively inhibits 11β-HSD1 reductase activity. Molec Cell Endocrin. 2003;212(1-2):41-49.

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High Cortisol: General Cortisol Calming Herbs

• Chamomile – commonly used as a tea • Pretty commonly known • Milky oat seed (Avena sativa) – 250-1000mg/day • Nervine, often used topically for skin conditions • Passionflower (Passiflora incarnata) – 250-500mg/day • Nervine, often compared to benzos in anxiolytic effect w/o side effects • Hemp-derived CBD – big topic requiring a separate lecture

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Citations: General Calming Herbs

• Akhondzadeh S, Naghavi HR, Vazirian M, et al. Passionflower in the treatment of generalized anxiety: a pilot double-blind randomized controlled trial with oxazepam. J Clin Pham Ther. 2001;26(5):363-367. • Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neurpsychopharmacology. 2011;36(6):1219-1226. • Blessing EM, Steenkamp MM, Manzanares J and Marmar CR. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics. 2015;12(4):825-836. • Ngan A and Conduit R. A double-blind, placebo-controlled investigation of the effects of Passiflora incarnata (passionflower) herbal tea on subjective sleep quality. Phytother Res. 2011;25(8):1153-1159.

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High Cortisol: Adaptogens • Ashwagandha (Withania somnifera) – 250-1000mg/day • Can be a thyroid stimulant, be wary with Graves, has calming/anxiolytic properties, ↑BDNF? • Siberian ginseng (Eleutherococcus) 250-500mg • Good general tonic, good for people who still have vitality but are a little depleted, ↑BDNF? • Rhodiola rosea – 100-500mg/day • Can be more stimulating than people think (dose dependent), can cause insomnia, can be drying (good for night sweats), neuroprotective, increase SIRT1, increases Hsp70, ↑BDNF? • Holy basil (Tulsi/Ocimum sanctum) – 250-1500mg/day • Nervine, anxiolytic

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High Cortisol: Adaptogens • Cordyceps sinensis (fruiting body) – 100-500mg/day • Stamina, improved physical health, contains beta-glucans (immune support)

• Schisandra berries (chinensis) – 500-2000mg/day (eat the berries) • Nervine but helps you feel focused/alert, improve cognitive health, liver protective, TCM uses it for liver heat (anger), increase Hsp70, increases glutathione • Bacopa monnieri – 200-600mg/day • Reduces brain inflammation, improve cognition, hyperactivity, attention, ↑BDNF

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Citations: Adaptogens

• Kean J, Downey L, Stough C. Systematic Overview of Bacopa monnieri (L.) Wettst. Dominant Poly-Herbal Formulas in Children and Adolescents. Medicines (Basel). 2017;4(4):pii: E86. doi: 10.3390/medicines4040086. • Mishra LC, Singh BB and Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev. 2000:5(4):334-346. • Nemetchek MD, Stierle AA, Stierle DB and Lurie DI. The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain. J Ethnopharmacol. 2017;2:197-92-100. • Panossian A and Wikman G. Effects of Adaptogens on the Central Nervous System and the Molecular Mechanisms Associated with Their Stress—Protective Activity. 2010;3(1):188-224. • Sowndhararajan K, Deepa P, Kim M, Park SJ and Kim S. An overview of neuroprotective and cognitive enhancement properties of lignans from Schisandra chinensis. Biomed Pharmacother. 2018;97:958-968. • Winston D and Maimes S. (2019) Adaptogens: Herbs for stress, stamina and stress relief. Healing Arts Press. • Xia N, Li J, Wang H, Wang J and Wang Y. Schisandra chinensis and Rhodiola rosea exert an anti-stress effect on the HPA axis and reduce hypothalamic c-Fos expression in rats subjected to repeated stress. Exp Ther Med. 2016;11(1):353-359.

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BDNF (Brain Derived Neurotrophic Factor) • Important for neuronal survival and development • Protects against glutamate toxicity • Big player in synaptic plasticity and neurotransmitter release • Heavily concentrated in hippocampus (learning, long term memory) • Also made by platelets, T-cells, monocytes/macrophages • Downregulation linked with: • Depression (esp. depression associated with hypercortisolism) • Alzheimer’s and other neurodegenerative disorders • PTSD • Epilepsy

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BDNF (Brain Derived Neurotrophic Factor) Glucocorticoids downregulate BDNF

Sangiovanni E, Brivio P, Dell’Agli M, Calabrese F. Botanicals as Modulators of Neuroplasticity: Focus on BDNF. Neural Plast. 2017;2017:5965371.

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What else increases BDNF? (not an exhaustive list)

• Exercise – especially strength training and HIIT • Deep sleep • Intermittent fasting/caloric restriction • Regular enjoyable socializing (social isolation ↓BDNF) • Zinc • Magnesium threonate • Omega 3 fatty acids • DHEA • Niacin • Magnolia

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Citations: BDNF • Abumaria N, Yin B, Zhang L, et al. Effects of elevation of brain magnesium on fear conditioning, fear extinction, and synaptic plasticity in the infralimbic prefrontal cortex and lateral amygdala. J Neurosci. 2011;31(42):14871-14881. • Arnason B (ed). (2010). NeuroImmune Biology (Chapter 21- Multiple Sclerosis and Depression: A Neuroimmunological Perspective. Amsterdam, Netherlands. Elsevier. • Figueiredo C, Antunes BM, Giacon TR, et al. Influence of Acute and Chronic High-Intensity Intermittent Aerobic Plus Strength Exercise on BDNF, Lipid and Autonomic Parameters. J Sports Sci Med. 2019;18(2):359-368. • Fu L, Doreswamy V, and Prakash R. The biochemical pathways of central nervous system neural degeneration in niacin deficiency. 2014;9(16);1509-1513. • Kumar PR, Essa MM, Al-Adawi S, et al. Omega-3 Fatty acids could alleviate the risks of traumatic brain injury - a mini review. J Tradit Complement Med. 2014;4(2):89-92. • Li F, Lu J, Li XM, et al. Antidepressant-like effect of magnolol on BDNF up-regulation and serotonergic system activity in unpredictable chronic mild stress treated rats. Phytother Res. 2012;26(8): 1189-1194. • Mattson MP and Wan R. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. 2005;16(3):129-137. • Nowak G, Legutko B, Szewczyk B, et al. Zinc treatment induces cortical brain-derived neurotrophic factor gene expression. Eur J Pharmacol. 2004;492(1):57-59. • Sangiovanni E, Brivio P, Dell’Agli M, Calabrese F. Botanicals as Modulators of Neuroplasticity: Focus on BDNF. Neural Plast. 2017;2017:5965371. • Zaletel I, Fillipovic D and Puskas N. Hippocampal BDNF in physiological conditions and social isolation. Rev Neurosci. 2017;28(6):675-692 • Zielinski MR, Kim Y, Karpova SA, et al. Chronic sleep restriction elevates brain interleukin-1 beta and tumor necrosis factor-alpha and attenuates brain-derived neurotrophic factor expression. Neurosci Lett. 2014;19:27-31.

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We’ve covered general high cortisol, Now let’s focus in on the CAR and PM cortisol

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High CAR = Consideration

• Talk with the patient about the morning of collection

• Did anything unusual happened that morning?

• Consider there might have been a situation

• ie. they woke with the flu, they were late to work that one morning, their child/partner/pet was a problem?  advise them NOT to test in this case

They might need to repeat the test

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High CAR:

Consider doing any “high cortisol” suggestions within 30min of waking for maximum impact And always address their sleep

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Addressing High PM Cortisol

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Inflammation at night causing insomnia?

• As cortisol naturally decreases through the day, the inflammatory (infection) “fire” is no longer dampened • This can cause more heat, pain, swelling…etc. in the evening • As a result, the HPA axis could increase to combat this Cortisol decreases Now cortisol is higher and naturally through the day you still can’t sleep Result? Inflammation & This turns the HPA infection increases axis back on Now you feel worse and can’t sleep

Cutolo M. Glucocorticoids and chronotherapy in rheumatoid arthritis. RMD Open. 2016; 2:e000203. doi: 10.1136/rmdopen-2015-000203 Hawking F. Circadian and other Rhythms of Parasites. Advances in Parasitology. 1975;13:123-182. 207

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Inflammation at night causing insomnia? • As cortisol naturally decreases through the day, the inflammatory (infection) “fire” is no longer dampened • This can cause more heat, pain, swelling…etc. in the evening • As a result, the HPA axis could increase to combat this

Cortisol decreases naturally through the day Now cortisol is higher and you still can’t sleep Result? Inflammation & This turns the HPA infection increases axis back on Now you feel worse and can’t sleep

If you know the cause of the inflammation/infection… address it, especially at night

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Remember, cortisol might be high for a reason. Don’t necessarily rush to lower it without understanding the cause. You might do more harm than good.

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High PM Cortisol: Lifestyle

• Avoid blue/white light 1-2 hours before bed • Wear blue light blocking glasses • Avoid alcohol and sugar before bed • Avoid caffeine intake in the afternoon and evening • Be aware of stimulatory exercise in the evening • Work on winding down 1-2 hours before bed • Take a bath, read a real book, relax with your family, journal, meditate • Sleep in a cool room temperature • Consider a sleep study evaluation for apnea or disordered breathing

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Caffeine Reminder: • Adenosine binding to the adenosine receptor  sleepiness • Caffeine inhibits or interferes with: • Adenosine receptors • GABA-A receptors A • Caffeine also activates Y Y the HPA axis Cell with Cell with adenosine adenosine receptor receptor

Bjorness T and Greene R. Adenosine and sleep. Curr Neuropharmacol. 2009;7(3):238-245. Ribeiro JA and Sebastiao AM. Caffeine and adenosine. J Alzheimers Dis. 2010; 20 Suppl 1:S3-15.

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High PM Cortisol: Calming Support Before Bed • Phosphatidylserine – 100-600mg • Major phospholipid class in the brain, important for neuronal signaling, improves membrane fluidity, mental stress, exercise induced stress, word recall and blunts ACTH response by adrenal glands • Magnesium: 250-500mg or Epsom salt baths • Does many things but supports GABA (with B6), ↑BDNF

• GABA support – major inhibitory NT in the brain • GABA – 250-1000mg/day • Pregnenolone – 10-100mg/day

• Abbasi B, Kimiagar M, Sadeghniiat K, et al. The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial.J Res Med Sci. 2012;17(12):1161-1169. • Km HY, Huang B and Spector A. Phosphatidylserine in the Brain: Metabolism and Function. Prog Lipid Res. 2014;Oct:1-18. • Pinna G, Uzunova V, Matsumoto K, et al. Brain allopregnanolone regulates the potency of the GABAA receptor agonist muscimol. Neuropharm. 2000;30(3):440-448 • Starks M, Starks S, Kingsley M, et al. . The effects of phosphatidylserine on endocrine response to moderate intensity exercise. J Inc Soc Sports Nutr. 2008;5(11):Published online 2008 Jul 28. doi: 10.1186/1550-2783-5-11

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High PM Cortisol: Calming Support Before Bed Amino Acids: • L-theanine – 200-600mg/day (drink organic matcha) • Relaxed alertness, often used for anxiety too (inhibits glutamate receptors, ↑BDNF) • 5-HTP – 50mg-300mg/day • Serotonin supportive but be careful if on antidepressant meds) • Tryptophan – 500-1000mg/day • Serotonin supportive but be careful if on antidepressant meds) • (L-taurine) – 250 – 3000mg/day • Calming to CNS as helps K, Na, Mg, Ca in/out of cells

Abbasi B, Kimiagar M, Sadeghniiat K, et al. The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial.J Res Med Sci. 2012;17(12):1161-1169. Pinna G, Uzunova V, Matsumoto K, et al. Brain allopregnanolone regulates the potency of the GABAA receptor agonist muscimol. Neuropharm. 2000;30(3):440-448.

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High PM Cortisol: Calming Specific for High 11b-HSD1

• Ziziphus vulgaris (Jujube) – 100-500mg/day (night) • Specifically good for those who can’t sleep through the night • Skullcap (Scutellaria baicalensis) – 250-500mg/day • Moderate to strong nervine and anxiolytic • Holy basil (Tulsi/Ocimum sanctum) – 250-1500mg/day • Nervine, anxiolytic

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High Cortisol: General Cortisol Calming Herbs

• Chamomile – commonly used as a calming tea • Milky oat seed (Avena sativa) – 250-1000mg/day • Nervine • Passionflower (Passiflora incarnata) – 250-500mg/day • Nervine, often compared to benzos in anxiolytic effect w/o side effects • Maca Lepidium – 1000-2000mg/day • Alkaloids affect hypothalamus and pituitary (reduces ACTH and thus cortisol) • Hemp-derived CBD – big topic requiring a separate lecture

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Moving on to Low Cortisol (formerly known as “phase 3 adrenal fatigue”)

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What is defined as “low cortisol?”

• Low free cortisol in more than 1 point or • Low for the 5-sample total of free cortisol or • Low free cortisol at 1 point with low metabolized cortisol or • Flat CAR (Cortisol Awakening Response)

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What is defined as “low cortisol?”

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Always Address Potential Root Causes: If the patient reports taking a shot to the head or violent car wreck, explore further before treating hypocortisol

• Head trauma/TBI affecting pituitary/hypothalamus

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Always Address Potential Root Causes: Actual case of confirmed CAH. Adaptogens aren’t likely to help in this case!

• Non-classical congenital adrenal hyperplasia (CAH)

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Additional Causes Specific for a Low CAR

• Hippocampal damage or atrophy • *the hippocampus controls the CAR • PTSD (mixed research but trends towards low cortisol) • Fluorescent lights

1. Bruehl H, Wolf O, and Convit A. A blunted cortisol awakening response and hippocampal atrophy in type 2 diabetes mellitus. Psychoneuroendocrinology. 2009;34(6):815-821. 2. Jung C, Khalsa S, Scheer F, et al. Acute Effects of Bright Light Exposure on Cortisol Levels. J Biological Rhythms. 2010;25(3):208-216. 3. Wessa M, Rohleder N, Kirschbaum M and Flor H. Altered cortisol awakening response in posttraumatic stress disorder. Psychoneuroendocrinology. 2006;31(2):209-215. 223

FYI: Causes of Hippocampal Damage/Atrophy • Long term stress • Childhood trauma • Lack of oxygen/hypoxia • Injury to head affecting hippocampus • MS, schizophrenia, epilepsy • PTSD • Depression • Diabetes • Longer duration of diabetes • Poorer glycemic control

1. Bruehl H, Wolf O, and Convit A. A blunted cortisol awakening response and hippocampal atrophy in type 2 diabetes mellitus. Psychoneuroendocrinology. 2009;34(6):815-821. 2. Driessen M, Herrmann J, Stahl K, Zwaan M, Meier S, Hill A, Osterheider M, Petersen D. Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization. Archives of General Psychiatry 2000; 57(12):1115-1122.

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Lastly, remember the cortisol feedback loop

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Over time, high cortisol can result in low cortisol Always keep this feedback loop in mind with chronic conditions

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Cortisol Progression in Chronic Ctates Moving from high to low cortisol

Treatment Considerations For low cortisol = depressed HPA

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Always Address Potential Cortisol Root Causes • Long-term stress/burnout • Sleep dysregulation • Hypothyroidism • Medications (glucocorticosteroids, opioids, Accutane, aspirin) • Chronic pain/infection = downregulation • Pituitary or hypothalamic dysfunction/lesion • Head trauma/TBI affecting pituitary/hypothalamus • Non-classical congenital adrenal hyperplasia • Surgical removal of adrenal gland • Addison’s disease

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Low Cortisol: Lifestyle • Start with the brain

• “HPA retraining” (my phrase – not a medical term) • Use adaptogens, nutrients, and brain support • Consider light therapy immediately on waking for the CAR • Sun/full spectrum lights • Light movement/exercise on waking

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If it all starts with the brain…

• Follow a strict circadian rhythm • Get your gut healthy and work on the vagus nerve • Improve blood flow and oxygen in the brain

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Increase Blood/Oxygen to the Brain

• Exercise – cardio, weights and inversion poses • Stop smoking • Normalize your blood sugar • Neurofeedback, bio-tuning, cranial-sacral work, energy medicine • Acupuncture/chiropractic/massage = upper back, shoulders, neck • HBOT – hyperbaric oxygen therapy • Post-TBI – increases oxygen levels in blood and tissues to improve brain repair • Test for iron overload (hemochromatosis) • Iron deposits can affect brain function • Reduce EMF/Cell phone to the head • In rats, 6 hours/day x 2 months = increased vacuolation in the brain (cellular vacuum and delivery). Cell phones also increase brain temperature.

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Citations: Brain

• Boussi-Gross R, Golan H, Fishlev G, et al. Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury - Randomized Prospective Trial. PLoS One. 2013;8(11):e79995. • Forouharmaid F, Ebrahimi H and Pourabdian S. Mobile Phone Distance from Head and Temperature Changes of Radio Frequency Waves on Brain Tissue. Int J Prev Med. 2018;9:61. • Shahabi S, Hassanzadeh I, Hoseinnezhaddarzi M, et al. Exposure to cell phone radiofrequency changes corticotrophin hormone levels and histology of the brain and adrenal glands in male Wistar rat. Iran J Basic Med Sci. 2018;21(12):1269- 1274. • Stankiewicz J, Panter S, Neema M, et al. Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications. Neurotherapeutics. 2007;4(3):371- 386.

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It all Starts with the Brain: Supplements • Bacopa monnieri – 200-600mg/day • Reduces brain inflammation, improve cognition, ↓hyperactivity, ↑attention,↑BDNF • Cordyceps sinensis (fruiting body) – 100-500mg/day • Increased learning and memory, eNOS, GABA and glutamate in the brain • Omega 3 fatty acids – 1000-3000mg/day • Rosemary – use as a spice, inhale the essential oil, drink the tea • Diterpine “has cognitive enhancing powers,” antioxidant, increases Nrf- 2 (phase 2 detoxification), protects against LPS damage, anti- inflammatory (inhibits TNF-a and IL-6), increases acetylcholine, will suppress iron absorption from the gut

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It all Starts with the Brain: Supplements

• Ginkgo biloba – 150-1500mg/day • Shown to affect recall, recognition, reaction time, attention, concentration through antioxidant effect, improved blood flow and neuroprotection, ↑ BDNF • Pyrroloquinoline quinone (PQQ) – 10-40mg (often paired with Co-Q10) • Increase nerve growth factor, protects NMDA receptors, antioxidant to peroxynitrite (improving mitochondrial health), reduces C-reactive protein and IL-6. • Maca Lepidium – 1000-2000mg/day • Alkaloids affect hypothalamus and pituitary (reduces ACTH and thus cortisol), antidepressant effect

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Citations: Brain Supplements

• Aguiar S and Borowski T. Neuropharmacological Review of the Nootropic Herb Bacopa monnieri. Rejeneration Research. 2013;16(4):https://doi.org/10.1089/rej.2013.1431 • Ehrlich S. (ed). Rosemary. Penn State Hershey A.D.A.M. 2017. Retrieved on September 11,2019 from http://pennstatehershey.adam.com/content.aspx?productId=107&pid=33&gid=000271 • Gonzales G. Ethnobiology and Ethnopharmacology of Lepidium meyenii (Maca), a Plant from the Peruvian Highlands. 2012. eCAM. Retrieved on September 11, 2019 from http://dx.doi.org/10.1155/2012/193496 • Habtemariam S. The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer's Disease. Evid Based Complement Alternat Med. 2016; 2016: 2680409. • Harris CB, Chowanadisai W, Mishuk DO, et al. Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects. J Nutr Biochem. 2013;24(12):2076-2084. • Hasiaguchi M, Ohta Y, Shimzu M, et al. Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia. J Pharm Health Care Sci. 2015;1(14):Published online 2015 Apr 10. doi: 10.1186/s40780-015-0014-7. • Jackson P, Reay J, Scholey A and Kennedy D. Docosahexaenoic acid-rich fish oil modulates the cerebral hemodynamic response to cognitive tasks in healthy young adults. Biology Psychology. 2012;89(1):183-190. • Liu Y, Wang J, Wang W, et al. The Chemical Constituents and Pharmacological Actions of Cordyceps sinensis. eCAM. 2015;retrieved on September 11, 2019 from https://doi.org/10.1155/2015/575063. • Nakano M, Murayama Y, Hu L, Ikemoto K, et al. Effects of Antioxidant Supplements (BioPQQ™) on Cerebral Blood Flow and Oxygen Metabolism in the Prefrontal Cortex. Oxygen Transport to Tissue XXXVIII. Advances in Experimental Medicine and Biology, vol 923. Springer, Cham. Retrieved September 11, 2019 from https://link.springer.com/chapter/10.1007/978-3-319-38810-6_29#citeas • Ohwada K, Takeda H, Yamazaki M, et al. Pyrroloquinoline Quinone (PQQ) Prevents Cognitive Deficit Caused by Oxidative Stress in Rats. J Clin Biochem Nutr. 2008;42(1):29-34. • Yuan G, An L, Sun Y, et al. Improvement of Learning and Memory Induced by Cordyceps Polypeptide Treatment and the Underlying Mechanism. Evidence based complementary and alternative medicine. vol. 2018, Article ID 9419264, 10 pages, 2018. https://doi.org/10.1155/2018/9419264.

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What Else is Helpful? Low cortisol treatment considerations

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Low Cortisol: General HPA Support

• A quality multi-vitamin is a good start but consider extra…

• B vitamins • Especially vitamin B5 (500mg) and B6 (P5P specifically: 10-50mg, watch neuropathy)

• Vitamin C – 100mg-1000mg/day • Remember dividing it up into smaller doses greatly increases absorption • Acts as an antioxidant in the adrenal gland • Humans don’t make their own vitamin C

• Magnesium – 250-500mg or Epsom salt baths • Needed for many things but also to make GABA with B6, ↑BDNF • Essential fatty acids – 1000-3000mg/day

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Low Cortisol: Adaptogens

• Ashwagandha (Withania somnifera) – 250-1000mg/day • Can be a thyroid stimulant, be wary with Graves, has calming/anxiolytic properties, ↑BDNF? • Siberian ginseng (Eleutherococcus) 250-500mg • Good general tonic, good for people who still have vitality but are a little depleted, ↑BDNF? • Rhodiola rosea – 100-500mg/day • Can be more stimulating than people think (dose dependent), can cause insomnia, can be drying (good for night sweats), neuroprotective and increases SIRT1, increases Hsp70, ↑BDNF?

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Low Cortisol: Adaptogens • Cordyceps sinensis (fruiting body) – 100-500mg/day • Stamina, improved physical health, contains beta-glucans (immune support) • Schisandra berries (chinensis) – 500-2000mg/day (or eat the berries) • Nervine but helps you feel focused/alert, improve cognitive health, liver protective, TCM uses it for liver heat (anger), increases Hsp70, increases glutathione • Bacopa monnieri – 200-600mg/day • Reduces brain inflammation, improve cognition, hyperactivity, attention, ↑BDNF

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Low Cortisol: Adaptogens

• Panax ginseng (Asian ginseng – red and white forms) – 100-500mg/day • Good tonic for the completely exhausted, could decrease glucose, increases acetylcholine, anti-inflammatory, can be heating and stimulating, ↑BDNF

• Licorice (Glycyrrhiza glabra) – 50-600mg/day • Inhibits 11b-HSD2 to increase cortisol • Watch for hypertension and hypokalemia

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Citations:

• Benzi IFF, Wachtel-Galor S. (2011). Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. Chapter 8 Biological Activities of Ginseng and Its Application to Human Health. Boca Raton, FL. CRC Press/Taylor&Francis. • Kean J, Downey L, Stough C. Systematic Overview of Bacopa monnieri (L.) Wettst. Dominant Poly-Herbal Formulas in Children and Adolescents. Medicines (Basel). 2017;4(4):pii: E86. doi: 10.3390/medicines4040086. • Mishra LC, Singh BB and Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev. 2000:5(4):334-346. • Nemetchek MD, Stierle AA, Stierle DB and Lurie DI. The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain. J Ethnopharmacol. 2017;2:197-92-100. • Panossian A and Wikman G. Effects of Adaptogens on the Central Nervous System and the Molecular Mechanisms Associated with Their Stress—Protective Activity. 2010;3(1):188-224. • Sowndhararajan K, Deepa P, Kim M, Park SJ and Kim S. An overview of neuroprotective and cognitive enhancement properties of lignans from Schisandra chinensis. Biomed Pharmacother. 2018;97:958-968. • Winston D and Maimes S. (2019) Adaptogens: Herbs for stress, stamina and stress relief. Healing Arts Press. • Xia N, Li J, Wang H, Wang J and Wang Y. Schisandra chinensis and Rhodiola rosea exert an anti-stress effect on the HPA axis and reduce hypothalamic c-Fos expression in rats subjected to repeated stress. Exp Ther Med. 2016;11(1):353-359.

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Low Cortisol: Glandulars

Adrenal glandular extracts may be considered, however there is limited clinical research available regarding their clinical impact

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Low Cortisol: Glandulars

Adrenal glandular extracts may be considered, however there is limited clinical research available regarding their clinical impact I tend to use adrenal glandulars in cases of low cortisol with really low vitality. I use them in the morning for 3-4 months then re-test Watch for side effects such as anxiety and insomnia

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What about cortisol supplementation such as cortef/hydrocortisone?

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We’ve covered general low cortisol, Now let’s focus in on the low CAR

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Low CAR = Consideration

• Talk with the patient about the morning of collection

• Did they miss the collection? Lay in bed a bit before collecting?

• Consider that there might have been a situation

• Poor sleep the night prior? Took steroids or aspirin at bed?

They might need to repeat the test

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Low CAR:

Consider doing any “low cortisol” suggestions within 30min of waking for maximum impact And always address their sleep

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Get sun or full spectrum light exposure first thing on waking

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Speaking of Light

Jung C, Khalsa S, Scheer F, et al. Acute Effects of Bright Light Exposure on Cortisol Levels. J Biological Rhythms. 2010;25(3):208-216. 250 250

For the record, the 10,000 lux suppressive study were fluorescent lights…like in your office

Jung C, Khalsa S, Scheer F, et al. Acute Effects of Bright Light Exposure on Cortisol Levels. J Biological Rhythms. 2010;25(3):208-216. 251 251

Natural Daylight vs Fluorescent

https://www.sunlightinside.com/light-and-health/natural-light-versus-artificial-light/ 252 252

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Natural Daylight vs Fluorescent

https://www.sunlightinside.com/light-and-health/natural-light-versus-artificial-light/ 253 253

What about DHEA? (Dehydroepiandrosterone)

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Zoom in on the adrenal gland: DHEA/DHEA-S

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DHEA and Metabolites on DUTCH

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DHEA versus DHEA-S

DHEA DHEA-S (active)

SULT2A1 gene Sulfotransferase enzyme STS gene Steroid Sulfatase enzyme (STS)

DHEA-S DHEA (active) DHEA-S is the sulfate ester of DHEA

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DHEA-S is the most abundant circulating steroid in the body

DHEA DHEA-S cannot cross into the brain versus via the blood brain barrier, can cross out once made from within DHEA-S the brain

DHEA-S has no diurnal pattern but DHEA (no S) has a diurnal pattern

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What does DHEA do? • Neurosteroid properties to protect CNS tissues from high cortisol, NMDA (glutamate), neuronal damage/death • Increases Brain Derived Neurotrophic Factor (BDNF) • Modulates dopamine and catecholamine release in the brain • Depends on region of the brain • Helps with mood, bone health, energy, and puberty • Increases acetylcholine • Can act as an anti-oxidant and anti-inflammatory • Lowers IL6 & TNFa

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DHEA and the “Phases of Adrenal Fatigue”

Despite what is commonly taught, we have found that DHEA is not that precise of a marker for HPA axis dysfunction due to the multiple causes of high/low levels coupled with its lack of a feedback loop

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Causes of Higher Total DHEA/DHEA-S • DHEA supplementation • Elevated cortisol • Increased STS enzyme activity = higher DHEA but lower DHEA-S • High levels found in endometriosis & breast cancer, increased with inflammation • Decreased sulfotransferase activity or inhibits SULT2A1 = higher DHEA but lower DHEA-S • Not enough PAPS (the universal sulfate donor) from low sulfate availability, low glutathione, low cysteine, low methionine, high acetaminophen or paracetamol use, PAPSS2 mutation (subset of PCOS), elevated DHEA and E2 inhibit SULT, inflammation and xenobiotics • Fasting (rat study fasting 14-16 hours) • PCOS • Adrenal tumor • High prolactin • Alcohol • Nicotine • Non-Classical Congenital Adrenal Hyperplasia • Medications: Alprazolam, Anastrozole, Methylphenidate, Amlodipine, Diltiazem and Bupropion. 261 261

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Inflammation Pattern with DHEA

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Causes of Lower Total DHEA/DHEA-S • Age – naturally declines with aging • HPA Axis dysfunction • Inflammation • Inflammation increases STS so higher DHEA but DHEA-S lower • Etiocholanolone and androsterone higher on dials than DHEA-S • SULT2A1 mutation • Higher DHEA but lower DHEA-S • Etiocholanolone and androsterone higher on dials than DHEA-S • Medications: • Glucocorticosteroids, Opioid pain medications, Pulmicort (inhaler) Oral birth control pills/oral Estrogen, Metformin/Glucophage

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High DHEA? • Address the cause • Are they on DHEA supplementation? • Address the HPA axis • Determine if it’s being protective or causing symptoms • Anxiety? Insomnia? Elevated 5a-reductase? PCOS? • Check the 5a-reductase preference • This pathway associated with hirsutism, androgenic acne, male pattern baldness and prostate problems

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Low DHEA?

• Supplementation for women: 2.5-10mg common dose • Supplementation for men: 10-50mg common dose • Be aware of side effects – check 5a-reductase preference • Support the HPA axis at-large

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Citations: DHEA • Ehrlich S (ed). Dehydroepiandrosterone. Penn State Hershey A.D.A.M. 2017. Retrieved September 11, 2019 from http://pennstatehershey.adam.com/content.aspx?productId=107&pid=33&gid=000299 • Goodarzi M, Carmina E, Azziz R. DHEA, DHEAS, and PCOS. 2015. 145(1):213-225. https://doi.org/10.1016/j.jsbmb.2014.06.003 • Higuchi K, Nawata H, Maki T, et al. Prolactin has a direct effect on adrenal androgen secretion. J Clin Endocrinol Metab. 1984;59(4):714-718. • Maninger N, Wolkowitz O, Reus V, Epel E, and Mellon S. Neurobiological and Neuropsychiatric Effects of Dehydroepiandrosterone (DHEA) and DHEA Sulfate (DHEAS). Front Neuroendocrinol. 2009 January; 30(1): 65–91. PMCID: PMC2725024 • Mueller J, Gilligan LC, Idkowiak J, Arlt W, and Foster PA. The Regulation of Steroid Action by Sulfation and Desulfation. Endocr Rev. 2015;36(5):526-563. • Mueller J, Idkowiak J, Gesteira T, et al. Human DHEA sulfation requires direct interaction between PAPS synthase 2 and DHEA sulfotransferase SULT2A1. J Bio Chem. 2018;293(25):9724-9735. • Sierksma A, Sarkola T, Eriksson CJ, et al. Effect of moderate alcohol consumption on plasma dehydroepiandrosterone sulfate, testosterone, and estradiol levels in middle-aged men and postmenopausal women: a diet-controlled intervention study. Alcohol Clin Exp Res. 2004;28(5):780-5.

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Summary Slide 1. Cortisol is important for many functions, but too high or too low levels creates dysfunction 2. Don’t miss Addison’s or Cushing’s – but you’re much more likely to see generalized HPA axis dysfunction 3. Testing is best done through a combination dried urine/saliva for comprehensive results 4. The CAR gives you extra insight into resiliency plus the CAR influences a number of processes in the body. 5. Cortisol metabolites allows you to have even more insight into your patient’s HPA story 6. DHEA is probably not the best marker for HPA axis dysfunction but it is primarily made in the adrenals and is important for overall health

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Summary Slide 1. Cortisol is important for many functions, but too high or too low levels creates dysfunction 2. Don’t miss Addison’s or Cushing’s – but you’re much more likely to Theresee generalized are a number HPA axis of evidence-baseddysfunction therapies to support 3. TestingHPA is axis best dysfunction, done through helpa combination prevent driedthe comorbidities urine/saliva for comprehensive results 4. The CAR gives youand extra improve insight overall into resiliency wellness plus the CAR influences a number of processesYou got in this! the body. 5. Cortisol metabolites allows you to have even more insight into your patient’s HPA story 6. DHEA is probably not the best marker for HPA axis dysfunction but it is primarily made in the adrenals and is important for overall health

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Case: 40yo female presents with morning fatigue and nightly insomnia • Married, mom of 2 kids (2yo and 4yo), runs a busy Etsy business • Symptoms getting worse over the last few years • She puts the kids to bed and works until late • Needs caffeine in the morning to ‘get going’ • Tried 3mg of melatonin at night – no help • Regular cycles – reports mild PMS for a week prior to starting • Eats “healthy,” stays hydrated, exercises sporadically • Takes fish oil, B vitamins and probiotics “sometimes” • Has a glass of wine 1-3 times/week – makes sleep worse

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Let’s assume for the sake of the case:

• Her iron is normal • Her thyroid is normal • Her vitamin D is normal • She does not report GI issues • It’s not a virus, mold or Lyme

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Case: 40-year-old female results

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Case: Where does she fall?

Spends a lot of her day on the Her PM cortisol is here lower end of the spectrum

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She’s clearly not Addison’s or Cushing’s but she does have HPA axis dysfunction

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Case: Interpretation • Metabolized cortisol = normal • production/metabolism not a problem • Pattern = She has a typical ‘low am/high pm’ presentation common with parents, students and entrepreneurs • Lower AM cortisol/CAR = fatigue, need for caffeine • Does have a CAR  it needs more power • High PM cortisol = insomnia

This puts her in a vicious cycle

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Case: Treatment  Recognize the Root Cause • She’s a busy mom of 2 with a successful online business • This requires her to fit in work when she can • As a result, she’s working at night activating her HPA axis • This affects her morning cortisol (CAR) • Some treatment options will be more of a ‘band aid’

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Case: Treatment

1. Do immediately on waking: • Adaptogens/Brain support/B vitamins/Vitamin C Consider ashwagandha, eleuthero, rhodiola, bacopa • Full spectrum light exposure while getting ready Open the curtains, get a full spectrum light box 2. At lunch, repeat adaptogens/Vitamin C 3. At night, maintain a sleep hygiene routine as best she can • Wear blue light blocking glasses while she works 4. Once the kids are in bed • 300mg phosphatidyl serine, 250mg magnesium threonate • Avoid wine

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Practitioner Heal Thyself

“You do not have to burn yourself out to keep others warm” ~Dr. Jones variation of popular quote with unknown author

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