About the Speaker. Bradley Bush, ND

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2 About the Speaker Dr. Bradley Bush is a registered Minnesota state licensed N.D. with a degree from National College of Naturopathic Medicine in Portland, OR. He is an owner and Clinical Director at Natural Medicine of Stillwater, a national lecturer on topics of neurotransmitter testing, neuro-endo-immunology and Lyme disease. He is a consultant to the natural products & laboratory industry. Dr. Bush is regularly published and sits on advisory boards to multiple company and non-profits. Dr. Bush lives in Stillwater with his wife and four daughters. Bradley Bush, ND

3 Goals of Lecture Review Hypothalamic-Pituitary-Adrenal Axis Appreciate the inter-consecutiveness of the neuro-endo-immune systems. Review the adrenal markers: ACTH, 17-HP, Cortisone, Cortisol, DHEA Discuss laboratory assessments to evaluate ACTH, 17-HP, Cortisone, Cortisol, DHEA Describe treatment variations based on laboratory test results

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6 Adrenal hormones are interconnected with other hormones

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8 Short-Term vs. Long-Term Stress Response

9 Increase cortisol activity should lead to a relieve the stressor and reduce its activity.

10 General Adaptation Syndrome Hans Selye 3 Phases Alarm Resistance Exhaustion

11 Adrenal Fatigue: A Three Stage Explanation Alarm Elevated: cortisol, DHEA, epinephrine, norepinephrine ACTH = High Serotonin High Resistance Cortisol High or Low DHEA High Epi = High or Low NE = High ACTH = High Serotonin= Normal Low Exhaustion Low: DHEA, cortisol, Epi, NE ACTH = High Serotonin = Low

12 Allostatic Load coined by McEwen and Stellar in 1993 Defined as the physiological consequences of chronic exposure to fluctuating or heightened neural or neuroendocrine response that results from repeated or chronic stress McEwen BS..Allostasis and allostatic load: implications for neuropsychopharmacology.neuropsychopharmacology Feb;22(2): Bruce S. McEwen. Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators.eur J Pharmacol April 7; 583(2-3):

13 Definitions Allostasis = the process of achieving stability, or homeostasis, through physiological or behavioral change. ( achieving stability through change ). Stress = a threat, real or implied, to the psychological or physiological integrity of an individual. Homeostasis = The ability or tendency of an organism or a cell to maintain internal equilibrium by adjusting its physiological processes ( standing still )

14 Clinical Significance The hormones and other physiological agents that mediate the effects of stress on the body have protective and adaptive effects in the short run and yet can accelerate pathophysiology when they are over-produced or mismanaged.

15 McEwen BS..Allostasis and allostatic load: implications for neuropsychopharmacology.neuropsycho pharmacology Feb;22(2): Bruce S. McEwen. Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators.eur J Pharmacol April 7; 583(2-3):

16 McEwen BS..Allostasis and allostatic load: implications for neuropsychopharmacology.neuropsychopharmacology Feb; 22(2): Bruce S. McEwen. Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators.eur J Pharmacol April 7; 583(2-3):

17 Negative feedbacks also takes place throughout the body including the brain.

18 Desensitization of cortisol receptors blunt negative feedback.

19 Oxidative stress is a cause and result of stress. metal toxicity chemical sensitives poor detoxication poly-pharmacy poor lifestyles smoking

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22 Stress Mediators adaption > pathophysiology Primary mediators Sympathetic NS = Cortisol, epinephrine, norepinephrine, DHEA Secondary outcomes Systolic and diastolic blood pressure Waist-hip ratio (also BMI) Serum HDL and total cholesterol HbA1c Tertiary outcomes Physical disease Mental disease Marian Joëls & Tallie Z. Baram.The neuro-symphony of stress.nature Reviews Neuroscience 10, (June 2009)

23 Adrenal Fatigue vs. Adrenal Insufficiency The term adrenal fatigue is not an universally accepted medical condition that has been used to explain a group of symptoms that result to due stress (mental and physical) and the bodies ability to cope with it. Symptoms of adrenal fatigue include: tiredness, trouble falling asleep at night or waking up in the morning, salt and sugar craving, and needing stimulants like caffeine to get through the day. These symptoms are common and non-specific, meaning they can be found in many diseases. They also can occur as part of a normal, busy life. Adrenal insufficiency is an accepted medical condition that occurs when our adrenal glands cannot produce enough hormones. Adrenal insufficiency is caused by damage to the adrenal glands or a problem with the pituitary gland. Symptoms of adrenal insufficiency include: dehydration, impaired cognition, or weight loss. He or she may feel weak, tired, or dizzy, and have low blood pressure. Other symptoms include stomach pain, nausea, vomiting, and/or diarrhea.

24 Conventional Adrenal Diagnostics Serum cortisol: rule out Cushing syndrome (high), adrenal insufficiency or Addison disease (low). 24-hour urine Cortisol: Adrenal insufficiency, Cushing disease, pseudohyperaldosteronism (due to excessive licorice consumption) Serum DHEA-S: General adrenal assessment, differentiate adrenal cancers, congenital adrenal hyperplasia, PCOS Serum Adrenocorticotropic Hormone (ACTH): Rule out Cushing disease, Cushing syndrome, Addison disease, hypopituitarism, secondary adrenal insufficiency Dexamethasone suppression: rule out Cushing syndrome. A high dose of dexamethasone exerts negative feedback on pituitary ACTH-producing cells, but not on ectopic ACTH-producing cells or adrenal adenoma. 24-Urine catecholamine and metanephrine: Rule out pheochromocytomas or a paraganglioma

25 Non-Conventional Adrenal Diagnostics Salivary cortisol (multiple points): Better assessment for diurnal adrenal variation. Salivary DHEA (both DHEA and DHEA-S) 24-hour urine assessment (all hormones and metabolites): total levels; usually run along with other steroidal hormones. Dried urine (multiple points): similar to 24-urine but showing diurnal variation. Urinary neurotransmitter: Spot collection

26 Strengths and Weaknesses Measures free (inbound) hormones Useful to collect multiple samples Salivary Testing Easy to collect (high patient compliance) Ideal for baseline testing Not reliable if taking or exposed to exogenous hormones. Not reliable in prepubescent children (cortisol and DHEA often lower) and less collection compliance. Some labs use FDA approved material, some use lab developed tests(ldt) (usually based of serum lab materials). Not useful to measure metabolites or track hormone therapies

27 Strengths and Weaknesses Serum Testing Often paid for by insurance. Single point collection does not provide diurnal variations. Stress of venipuncture may lead to falsely elevated values. Not a functional stress measurement due to invasive collection, travel to venipuncture location and possible diet/ lifestyle activity prior to venipuncture. Reference levels are designed to rule out Addison s, Cushing s and tumors.

28 Strengths and Weaknesses 24-Urine Testing Can measures bound hormones and metabolites. Not as easy to collect (lower patient compliance). Ideal to monitor hormone therapies and evaluate metabolites. LDT using multiple different platforms.

29 Strengths and Weaknesses Dried Urine Testing Can measures bound hormones and metabolites. Not easy to collect (lower patient compliance). Ideal to monitor hormone therapies, evaluate metabolites and their diurnal variations. LDT with limited validation.

30 DHEA Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, together represent the most abundant steroid hormones in the human body. Adult humans secrete both DHEA and DHEAS from the zona reticularis of the adrenal cortex and also DHEA from the ovary and testis

31 Strengths and Weaknesses DHEA-S and DHEA DHEA-S is a large molecule with limited diffusion into salivary gland Most salivary DHEA-S tests are LDT based off of serum lab materials. Free form of DHEA has more functional variation than DHEA-S. Pregnenolone is converted into DHEA by the enzyme cytochrome P450c17; this single enzyme catalyzes multiple reactions.

32 DHEA Comments An easy add-on to most serum orders. Salivary DHEA has less interfering factors as DHEA-S. Most commonly measure as a morning baseline. Mostly stable throughout day with slight decrease in levels in evening. Not typically worth re-running more than once daily. Temporary increase levels seen in progressively worsening adrenal fatigue (often correlating with lowering of cortisol values); classic mid-stage adrenal fatigue. Can become suppressed with hydrocortisone (Cortef) usage.

33 17-hydroxyprogesterone (17-HP) 17-hydroxyprogesterone (17-HP) is a precursor to cortisol. Often used as part of a 17- HP: cortisol ratio; determine if adrenals are not producing enough (adrenal fatigue). Measured in serum and urine.

34 Cortisone Evaluated to determine abnormalities of 11-beta-hydroxy steroid dehydrogenase (cortisol to cortisone ratio). 2:1 to 3:1 is seen in normal patients. Licorice root (glycyrrhizic acid) and carbenoxolone (synthetic glycyrrhizic acid) may suppress ratio (<1). Glycyrrhizic acid inhibits 11B-HSD2 enzyme. Corosolic acid inhibits 11B-HSD1 enzyme. Banaba extract, loquat leaves, rosemary extract. Usually measured in urine.

35 Glycyrrhizic acid My rule of thumb is that it can increase cortisol levels by 40%, typically in 4 days. Contraindicated in patients with HTN (will also boost mineralocorticoids). Dosing mg glycyrrhizic acid am and/or noon (qd or BID). Need greater than 40% boost? Then hydrocortisone (Cortef) 2.5 mg - 10mg with or without licorice root. Higher cortisol in evening, be sure to only dose in am.

36 Corosolic acid Banaba root ( mg daily; which typically provides mg of corosolic acid daily. Strong antioxidant Shown to reduce lipids and blood glucose levels Dose early evening and bedtime (1 hour before) for 1-2 weeks, then shift to bedtime (1 hour before).

37 Cortisol Diurnal variability of cortisol makes multi-point salivary cortisol assessment preferred to assess for adrenal fatigue.

38 Cortisol Never assume cortisol is elevated only due to psychological stress.

39 Prolonged stress can reinforce pregnenolone to cortisol pathway, resulting in less sex hormones produced.

40 Pregnenolone steal Early signs of shunting Increased cortisol pathway activity Less sex hormone production 24-Hour Urine Test Result

41 Pregnenolone Steal Treatment Options Reduce cortisol levels: (corosolic acid) Improve liver hormone detox pathways: Calcium D-glucarate and Diindolylmethane (DIM) Any additional liver support as needed bhrt of progesterone and Biest used short term Rule out SIBO

42 PCOS with elevated Cortisol (18 yo female) Goals are to reduce hormone levels, reduce cortisol activity, boost progesterone, and rule out SIBO

43 To Suppress Cortisol or Not Autoimmune no sxs Ask yourself? Is cortisol reducing the immune system activity in a beneficial way? e.g. #1 Fatigue no sleep issues Are elevated cortisol levels resulting in symptoms like anxiety or insomnia? e.g. #2 Are elevated cortisol levels resulting in symptoms Focus issues, weight gain? e.g. #3 Anxiety, Focus issues Weight gain, Poor sleep

44 Consider Immune System s Status when Evaluating Cortisol Inflammatory/immune testing: hs- CRP, Myeloperoxidase (MPO), fibrinogen Antibodies: thyroid, food (IgE and IgG), infectious, etc. Autoimmune screenings: Antinuclear antibody screen (ANA) Rule out chronic infections: dental issues, SIBO, vector born illness, stealth viruses, etc.

45 69 yo Female with Interrupted Sleep Insomnia was the first symptom of refractory Borreliosis.

46 Cortisol spiking after eating Cor$sol spikes post lunch and dinner Morning sample is fas$ng 62 yo female with CF/FM, anxiety, and insomnia. SIBO pos. (very high methane and moderate elevated hydrogen levels) 16 yo female with severe anxiety, insomnia and fatigue. SIBO pos. (very high hydrogen and slightly elevated methane levels)

47 Example of SIBO test: Lactulose Breath Test (hydrogen and methane) 62 yo female with CF/FM, anxiety, and insomnia. SIBO pos. (very high methane and moderate elevated hydrogen levels)

48 Clinical Pearls Thyroid activity is directly and indirectly effected by cortisol. Cortisol: Inhibits TSH (lead to falsely lower TSH levels) Decreases active hormone ft3 levels (reduces T4 to T3 conversion)

49 Is serum cortisol worth running to diagnose and/or manage adrenal fatigue? If insurance covered, it is always worth running; in addition to DHEA-S. Very low salivary cortisol levels should be followed up with serum cortisol and DHEA-S to rule out Adrenal insufficiency/ Addison s disease. Very high salivary cortisol levels should be followed up with serum cortisol and DHEA-S to rule out Cushing s syndrome. 24-hour urine is also used as follow up.

50 Laboratory Pearls Large molecules can not be accurately measured in saliva; therefore certain lab markers have very questionable utility including: SIgA, gliadin antibodies and to a lesser extent DHEA-S. If your serum sample was transported in mail to lab for testing, retest abnormal hormone levels with local lab before referring to endocrinologist for follow up.

51 Adrenals or More than just Hormones You get a greater view of the HPA axis, when you expand your view to include adrenal neurotransmitters and those that impact its activation.

52 Take away messages Salivary 4-Point cortisol with DHEA is preferred functional test for adrenal hormone assessment. Serum cortisol and DHEA-S should also be run if very low or very high cortisol/ DHEA activity is suspected or ID d through saliva testing. 24-hour urine/ dried urine testing can measure cortisol precursors and metabolites and determine if associated with other hormone imbalances. Elevations of cortisol is a healthy response to immune/ inflammatory stress. Must rule out inferring factors and consider state of immune system when diagnosing off cortisol activity. Adrenal assessment based on just adrenal hormones is limiting and additional testing may be needed.

53 CONTACT DR. BUSH 105 New England Place, Ste. 220 Stillwater, MN