Download The Thyroid, Adrenal Pancreas Connection

ADRENAL-THYROID-PANCREAS
CONNECTION
Benjamin S. Gonzàlez, MD
Medical Director
Atlantis Medical Center
Silver Spring, MD
Assumptions In The Interest Of Time
• You Know the Basics of the Endocrine System
• This is Based on Literature and Experience
• Physicians have Preconceptions
• Linear vs Systems Thought Processes
• Modern Medicine is Disease Focused
• Dogma vs Truth and the Shades Between
• This is NOT a Comprehensive Discussion
• 2 hr lecture in 45 minutes
• A Few Busy Slides
• You Have My Bio
Adrenal-Thyroid-Pancreas Connection
• Discuss Clinical Effects of Excessive HPA-axis
•
•
•
•
•
activation
Understand the link between the Adrenal, Thyroid,
and Pancreas (A-T-P)
Review how Stress, Metabolism, and Sugar are
linked in the approach of patient energy and vitality
Discuss a biology systems approach in assessing
future health risk (MetS, Sleep, CVD)
Review issues with focused organ treatment
If Time: Bring in a Little Nutrition
Adrenal-Thyroid-Pancreas Connection
• What will be missing:
• In depth detailed marker/hormone structure
discussion
• Detailed Testing Discussion
• Treatment of A-T-P connection imbalances
Adrenal-Thyroid-Pancreas Connection
• A-T-P Connection is a Systems of Vitality and
Energy
• When it’s GOOD
• Energy is great, stress in balance, you have a
general feeling of well being
• When it’s BAD
• Fatigued, weight gain, sluggish
• This is a fluid model of systems
• NOT Linear!
Adrenal-Thyroid-Pancreas Connection
• Our Systems act together in an Elegant Dance
of Physiology
Normal Physiology
Adrenal-Thyroid-Pancreas
Regulation of
protein, carb, lipid
and nucleic acid
metabolism
Anti-inflammatory
Energy Production
Metabolism
Regulation
Converts Glucose to
Glycogen
Protein Synthesis
Limits Fat and
Protein to Glucose
Growth and Activity
of Nervous System
Facilitates cell
uptake of Glucose
Adrenal-Thyroid-Pancreas Connection
• EXERCISE as an example
• Moderate vs Intense
• Moderate: Improves mood, sugar metabolism,
oxygenation of tissues, increases enzymatic fat
burning activity
• Intense: Increased cortisol, dysglycemia, amino
acid deficits, immune stress, create catabolic
metabolism, and proneness to injury
Clinical Effects of Excessive HPA axis Activation
OUTCOMES?
Adapted from: Endocrinology and Metabolism Clinics of North America, Elsevier Publishing, ed. Anne R. Cappola. June 2013, vol. 42, no. 2.
Clinical Effects of Excessive HPA axis Activation
• OUTCOMES?
• Stress Response AHHHHHHHH!!!!!
• Sarcopenia, osteopenia, sydrome X, immunological
compromise, cognitive decline, frailty, CVD, etc.
• Chronic Stress
• Increased Allostatic Load
Hormones and Neurotransmitters
Adrenal
Thyroid
Pancreas
Adrenal Glands
Adrenal Glands Produce over 50 Hormones:
Cortisol and Aldosterone most abundant
ADRENAL CORTEX
ADRENAL MEDULA
Zona Glomerulosa: Aldosterone
Epi: 80%
Zona Fasiculata: Cortisol
Zona Reticularis: Androgens,
pregnenolone, progesterone
Norepi: 20%
CORTISOL
• The “Stress Hormone”
• Regulated by hypothalamis-pituitary-adrenal
(HPA) axis
• Cortisol levels follow a circadian rhythm in
metabolic homeostasis
Thank You Dr. James LaValle
Chronic CORTISOL Elevation
•Increased insulin secretion
•Increased fat deposition
•Alteration in immune function
•Muscle wasting
•Hypothyroidism (adrenal exhaustion)
•Memory loss
•Alteration in sex hormones
•Loss of REM, mental and emotional instability
•Increased blood lipids, plaque formation, CVD
•Receptor site activation of tumor cells
Thank You Dr. James LaValle
Normal Diurnal Hormonal Level
Thank You Dr. James LaValle
CORTISOL
• Mediators of Homeostasis and Stress
McEwan BS, et al. Protective and Damaging effects of stress mediators. Dialogues Clin Neuro Sci. 2006 Dec; 8(4): 367-81
CORTISOL
• Mediators of Homeostasis and Stress
McEwan BS, et al. Protective and Damaging effects of stress mediators. Dialogues Clin Neuro Sci. 2006 Dec; 8(4): 367-81
CORTISOL Allostatic Load
• Sleep Deprivation
• Metabolic Syndrome Effect(1)
• Autoimmune Trigger
• CVD(2)
• MS Trigger(3)
• Cancer Trigger(4)
• Osteoporosis and Vit D deficiency(5)
1.)Kazakou P, et al. Activated hypothalamic pituitary adrenal axis in patients with metabolic syndrome. Horm Metab Res.
2012;44(11):839-44.
2.)Lazzarino AI, et al. The association between cortisol response to mental stress and high-sensitivity cardiac troponin T plasma
concentration in health adults. J Am coll Cardiol. 2013;62(18):l1694-1701.
3.)Kern et al. Cortisol awakening response is linked to disease course and progression in multiple sclerosis. PLoS One. 2013;8(4):e60647.
4.)Du YJ, et al. Sputum inerleukin-6 tumor necrosis factor-alpha and salivary cortisol as new biomarkers of depression in lung cancer
patients. Prog Neuropsychopharmacol Biol Psychiatry. 2013;47:69-76.
5.)Lee P. Vitamin D metabolism and deficiency in critical illness. Best Pract Res Clin Endocrinol Metab. 2011;25(5):769-81.
Boling EP. Secondary osteoporosis: underlying disease and the risk for glycocorticoid-induced osteoporosis. Clin Ther. 2004;26(1):1-14.
CORTISOL and Metabolic Syndrome
• Metabolic Syndrome (MetS) associated with
elevated morning SERUM cortisol levels
• MetS associated with HPA-axis dysregulation
• Central and peripheral level issues
• Elevated Long Term Cortisol Levels
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•
•
2013 Study n=1258 16- 64 y/o
Hair study (good for long term studies)
Higher prevalence of MetS
1.)Kazakou P, et al. Activated hypothalamic pituitary adrenal axis in patients with metabolic syndrome. Horm Metab Res.
2012;44(11):839-44.
2.)Anagnostis P, et al. Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis.
J Clin Endocrinol Metab. 2009;94(8):2692-701.
3.)Stalder T, et al. Cortisol in hair and the metabolic syndrome. J Clin Endocrinol Metab. 2013;98(6):2573-80.
CORTISOL and CVD
•2013 Clinical Study
(n=508, mean age 62.9 + 5.7yr) No prior CVD evidence
•Significant association between cortisol response
and detectable high-sensitivity cardiac troponin T
(hs-cTnT)
1.)Lazzarino AI, et al. The association between cortisol response to mental stress and high-sensitivity cardiac
troponin T plasma concentration in health adults. J Am Col Cardiol. 2013;62(18):l1694-1701.
CORTISOL and CVD
•2012 Clinical Study
•n=466 avg. age 62.7 y/o male and female
•No
h/o CVD
•Baseline Salivary Cortisol Levels done
•Followed for 3 years
•Results:
Increased Stress, Increased Cortisol correlated directly
with significant increased risk of coronary artery
calcification
1.)Hamer M, et al. Cortisol responses to mental stress and the progression of coronary artery calcification in healthy men
and women. PLoS One. 2012;7(2):e31356.
CORTISOL and CVD
▪2006 CARDIA study
▪n=718 avg. age 40
▪Results:
▪Flattest diurnal cortisol slope quartile were > 3 times more
likely to have coronary calcification
▪Independent of socio-economic status
▪Independent of established CV risk factors
1.)Matthews K, et al. Diurnal cortisol decline is related to coronary calcifications: CARDIA Study. Psychosom
Med. 2006;68:657-661.
CORTISOL and CVD
•2013 Clinical Study
n=450 obese children and adolescents, ages 4-18
•ACTH and Cortisol levels positively associated with inc.
systolic and diastolic BP, triglycerides, fasting glucose, and
insulin resistance
•Cortisol (Not ACTH) positively associated with increased LDLcholesterol
•SUMMARY: high morning ACTH and cortisol levels are
associated with cardiovascular risk factors
1.)Prodam F, et al. High-end normal adrenocorticotropic hormones are associated with specific cardiovascular risk factors
in pediatric obesity: a cross-sectional study. BMC Med. 2013;11:44.
CORTISOL and CVD
•Hair Cortisol predictive of Future Heart Disease Risk
•112 adults
•295.3ng/g active MI cases
•224.9ng/g control
•Controlling for all AMI factors Hair Cortisol was the
strongest predictor of AMI
~~Gotta Ask: How many
Cardiologists measure cortisol?
1.) Pereg et al., Stress: Vol.14 Issue 1 p. 73-81 January 2011
CORTISOL and Sleep
• Sleep and Cortisol Release
• Controlled in slow-wave sleep
•
By decreases in corticotropin-releasing hormone (CRH)
and increases in GH
• Increase Stress
•
•
•
•
•
1.)
HPA-axis dysfunction, disruption of diurnal patter of
GH, CRH, ACTH release
Results in a paradoxical rise of nocturnal cortisol levels
Sleep phase dysfunction
Nocturnal hypercortisolism
Feeds into itself increasing cortisol even more
CORTISOL and Exercise
• Hyper/intense exercise without counter-
measures drives up cytokine/inflammatory,
metabolic “dysbalance”
• People don’t appreciate the term “moderate
exercise”
1.)
CORTISOL
• Prime Target in Approach to Healing metabolic
Homeostasis?...
• The Circadian Rhythm
• Elevated serum Cortisol produces an overall
net acid effect
• Blood pH homeostasis actually become
detrimental to overall physiology
• Mg and Ca pool is depleted to help buffer blood pH
Chrousos, G. P. Organization and integration of the endocrine system: the sleep and wakefulness
perspective. Sleep Med. Clin. 2, 125–145 (2007)
Adrenal-Thyroid-Pancreas Connection
• Adrenal Glands and Chronic Stress:
• Elevated Cortisol:
• DHEA Levels Decrease
•
•
Now Focused on Stress
Sex Drive drops-changes making testosterone, Progesterone, etc.
• Seratonin Levels Decrease
•
Depression, anxiety, cravings for sugar/carbs, “flat” feeling
• Melatonin Levels Decrease
Melatonin and Insulin Regulation
Melatonin influences insulin secretion via the Gprotein-coupled at MT1 and MT2 receptors
•Interferes with insulin secretion from beta cells and
transmitting circadian timing information to the islets
•Circadian insulin secretion is adapted to day/night
changes via melatonin-dependent synchronization
Melatonin regulates blood sugar and circadian
insulin secretion
THUS: SLEEP IS OFF, BLOOD SUGAR DISRUPTED,
DIABETICS
Peschke E, et al. New evidence for a role of melatonin in glucose regulation. Best Pract Res Clin Endocrinol
Metab. 2010;24(5):829-41.
Adrenal-Thyroid-Pancreas Connection
• Adrenal – Thyroid Connection Closely Linked
• Both under hypothalamic control/tropic hormones
• Thyroid competes with adrenals for tyrosine
• Chronic stress……increased cortisol….dec thyroid
• Not enough tyrosin for T3/T4 production
• Under stress body unable to convert from
phenylalanine
1.) Melmed: Williams Textbook of Endocrinology, 13th ed. Philadelphia, PA:
Saunders Elsevier; 2015
Adrenal-Thyroid-Pancreas Connection
• Adrenal – Thyroid Connection
• Increased Cortisol Output
•
•
•
•
1.)
Inhibits 5’deiodinase limiting T3 production from T4
TRH unregulated to form more T4
Alters metabolism of fats, sugars, and proteins
Adrenal-Thyroid-Pancreas Connection
•
•
1.)
rT3 Binds to T3 receptors
Blocks T3 from binding!
Exercise Intensity and Thyroid Function
• 2005 Clinical Study
• n=60 male well trained athletes
• Compared thyroid hormone levels at 45%, 70% and
90% of max HR
• TSH, T4 and fT4 levels increased at 70 and 90% vs.
45%
• fT3 and T3 increased at 70%, but fell at 90%
• Thought to be due to elevations in cortisol
Ciloglu, F., Peker,I. et al. Exercise intensity and its effect on thyroid hormones Neuroendocrinology Letters No.6
December Vol.26, 2005
How Insulin Receptor Should Work
Thyroid-Pancreas and PGC-1 α
•T3 regulates PGC-1α (1)
•PGC-1α co-activates the thyroid receptor
• PGC-1α stimulates hepatic gluconeogenesis and
fatty acid oxidative metabolism(2)
• PGC-1α increases the expression of GLUT 4 in
skeletal muscle.
•Increases glucose uptake in cells
~PGC-1α expression reduced in obesity/DM-T2/IR(3)
1.)Cell Press :T3 mediated expression of PGC-1αvia a far upstream located thyroid hormone response
element 2008 Elsevier
2.)Liang H, et al. PGC-1: a key regulator of energy metabolism. Advan Physiol Edu. 2006;30:145-151.
3.)Handschin C, Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1
coactivators, energy homeostasis, and metabolism.Endocr Rev. 2006 Dec;27(7):728-35. Epub 2006 Oct 3.
Review.
Depressed Thyroid
Adrenal-Thyroid-Pancreas
Cholesterol to
pregnenolone
Loss of
mitocondrial
numbers AND
output
Low ATP
production
OTHER:
Depressed Cognition
Reduced Cardiac
Function
Slowed Gastric
Motility
Insulin resistance
Inc. oxidative stress
Inc. lactic acid
production
Insulin Dominance
Adrenal-Thyroid-Pancreas
Activated/Stress
Wired and Tired
Poor Sleep
Central Obesity
Mind Racing
Depressed
Cold Intolerance
Weight Gain
Poor Cognition/Mood
Post Parandial Fatigue
Sluggish
Heavy/Slow
Carb Cravings
Irritability/Shakiness
Recurrent Infections
Insulin Dominance Lab Look
Adrenal-Thyroid-Pancreas
Slightly elevated
cortisol
NL to Slightly
elevated TSH
Elevated fasting
Insulin or challenge
Depressed T4/T3
Elevated Fasting
Glucose
No TPO or
thyroglobulin Abs
Elevated Liver
Enzymes
Insulin Dominance
• Insulin
• Cortisol mobilizes liver glycogen
• Decrease insulin sensitivity
• Increases TNF alpha directly
• Testosterone
Labs Assessing Impact
•Avg pH(salivary and urinary) Ideal > 6.8
•Sodium 140 ideal
•RBC Mag 5.8
•Potassium > 4.5
•Serum Cortisol 10-15
•Salivary 4 point Cortisol
•SIgA varies but should be 3rd quartile
•DHEA 105-700 at least 300
•IGF-1
•Blood Glucose/Insulin
(Don’t Forget BP and Resting am Pulse < 70 )
Supplement Recommendations
Adrenal-Thyroid-Pancreas
Selenomethionine,
Chromium, Coleus
Chromium, Vit D,
Forskohli, 7 Keto DHEA
Vitamin C, Adrenal
Ashwaganda, Rhodiola, Magnesium, Alpha
Cortex Extract, N.
Lipoic Acid, Fish
Schisandra, Ginseng
Medulla, Holy Basil
M,A&S), Eurycoma
oil, Bitter Melon,
PharmaGABA,
Longifolia,
Cinnamon,
Magnolia/Phellodendron
Neuromedulla glandular,
Arginine, Vanadium, L-theanine, Sterols &
DHEA
sterolins
Benfotiamin,
Tryptophan/5HTP
Selenium
Cordyceps sinensis
(Iodine, tyrosine, ferritin)
Not Even CLOSE
• Not a Single Word:
• Treatment
• Other Endocrine Systems Dance with A-T-P
• Diet (i.e. Intermittent Fasting as a powerful tool)(1)
• Practical Usefulness of Markers
•
HINT: Learn/Know PGC-1alpha(1)
• Dominance of Each Organ System
• Bone Disease, Cancer Risk, Obesity, etc.
• How Saliva and Urine pH can be powerful tools
1.)Psilander N, Frank P, Flockhart M, Sahlin K. Exercise with low glycogen increases PGC-1a gene expression in
human skeletal muscle. Eur J Appl Physiol. 02 Oct 2012
Quick Clinical Pearls
• Think ACTUAL Underlying Issue
• Think Diurnal Cortisol Disruption
• Look Up-Stream
• If treating a system and Tx is not working?
• “Adrenal Fatigue?” Not so much
• HPA-axis no longer signals adrenals
• Centrally Mediated Effect
• L-Carnitine 2-4 grams a day regulates T3 and T4 entry
into the cell helping to modulate hyperthyroid state
Thank You!
CORTISOL and Exercise
1.)
Adrenal-Thyroid-Pancreas Connection
CORTISOL and Multiple Sclerosis
•2013 clinical study (n=111); 77 patients with multiple
sclerosis (MS), 34 control
•Diurnal cortisol release assessed – salivary
•Neurological ability rated by Kurtzke's Expanded
Disability Status Scale (EDSS)
•Circadian cortisol release including cortisol
awakening response associated with relapsingremitting MS
Kern et al. Cortisol awakening response is linked to disease course and progression in multiple sclerosis. PLoS
One. 2013;8(4):e60647.