Understanding the HPA-T Axis with Relation to Hormone Imbalance

1. Understanding the HPA-T Axis with Relation to Hormone Imbalance R.W. Watkins, MD, MPH, FAAFP Sanesco Roundtable 4 May 2013 Charlotte, NC

2. Introductions • R.W. “Chip” Watkins, MD, MPH, FAAFP • Past-President and Board Chair – NCAFP • Assoc Prof of Family Medicine – UNC, ECU • Chief Medical Officer, SanescoInternational • President/Lab Director, NeuroLab, Inc. • President/CEO, NCHealthSPAN, Inc. • Former Medical Director, GenovaDx and Great Smokies Diagnostic Lab, Asheville, NC

3. Introductions

5. Learning Objectives • Develop an overview of the interconnectedness of the neuroendocrine communication system • Identify the major neurotransmitters and their function • Understand the balance between inhibitory and excitatory neurotransmitters and their relationship to hormonal imbalances such as PMS and menopausal symptoms

6. Overview • Neurotransmitters • Hormones • Thyroid hormones • Adrenal hormones • Sex hormones • Understanding the inter-relationships between them

7. Neuronal Pathways • Optimal function dependent upon balanced NT release and reuptake in the synapse • NT release must be adequate or the communication cannot continue • Imbalance of the Neuro-immuno-endocrine Communication System can lead to many pro-inflammatory degenerative diseases • Imbalance in the Communication System can contribute to hormonal imbalances

8. Neurotransmitters: The tip of the iceberg

9. CBC SMAC 20 with lipids TSH, fT3 , fT4, rT3 Thyroid auto-antibodies Estradiol (E2), Progesterone Free & Total Testosterone DHEA-S Pregnenolone FSH, LH SHBG (Sex Hormone Binding Globulin) TBG (Thyroid Binding Globulin) DHT (Dihydrotestosterone) 2:16 Estrogen Metabolite Ratio Iodine levels (24 hr. urine) Mammography Pap Smear DEXA scan of hip and spine PSA (males) Prolactin (if indicated) Sonography (if indicated) Intracellular minerals 3-Hour GITT: Insulin Resistance Test Neurotransmitter levels (spot urine sample) AI: Adrenal Index (saliva) Natural Hormones: Evaluation for NT-HRT H & P and laboratory Test in luteal phase, if still menstruating

10. Serotonin GABA Glutamate Dopamine Norepinephrine Epinephrine Common Neurotransmitters These top “BIG 6” are measured initially to assess a person’s neurotransmitter balance

13. How can I use this information? • Initial Assessment of patient • What is the current state of their nervous and hormonal systems? • Helps you guide therapy • Is patient on SSRI or SNRI? • Other medications that can effect NTs? • Helps you monitor patient progress • Helps you maintain patient improvements

14. Early Research on NTs • Research began in the 1960’s-1980’s • Suggested that increasing levels of NTs, especially Serotonin, was found to improve mood disorders - particularly depression and anxiety • Increased understanding of Biochemical Pathways • Amino Acids precursors to Neurotransmitters • Amino Acid Therapy • Pharmaceutical research suggested drug-based mechanisms for neuromodulation • SSRI’s (Prozac 1987) • SNRI’s. (Wellbutrin 1989, etc.)

16. Neurotransmitter Balancing“Filling the Tank” • Only amino acid precursors are able to replete NT reserves • SSRI’s/SNRI’s do not “fill the tank” but rather improve NT function by slowing NT reuptake • Appropriately balancing hormones will make NT’s work more efficaciously

17. Neurotransmitter Pathways“Serotonin” Pathway for serotonin and melatonin synthesis from tryptophan. Abbreviations: THP = tryptophan hydroxylase, 5-HTP = 5-hydroxytryptophan, AADC = aromatic L-amino acid decarboxylase, SNA = serotonin N-acetylase, HOMT = hydroxyindole-O-methyltransferase

18. Serotonin • 5-HT or 5-hydroxytryptamine • 1-2% in CNS • 95% in gut enteric nervous system • 2-3% in platelets • 5-HT acts as an inhibitory neurotransmitter • 5-HT acts as a neuromodulator • Affects glutamate excitability over diverse regions of the CNS • Acts by stimulating its own receptors on GABA neurons prompting GABA to perform its inhibitory function • Acts to inhibit the release of the catecholamines (“CATS”): dopamine, NE, epinephrine

19. 5-HTP has been used clinically for over 30 years. In addition to depression, the therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including fibromyalgia, insomnia, binge eating associated with obesity, cerebellar ataxia, and chronic headaches. 5-HTP easily crosses the blood–brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. Supplementation with 5-HTP is hypothesized to normalize serotonin synthesis, which is putatively related to its antidepressant properties. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther. 2006 Mar;109(3):325-38. Review. T.C. Birdsall, 5-Hydroxytryptophan: a clinically-effective serotonin precursor, Altern Med Rev3 (1998), pp. 271–280.

20. Serotonin and Thyroid • Diurnal TSH peak found to be serotonin-dependent. Jordan D, et al. Endocrinology. 1979 Oct;105(4):975-9. • Giving 5-HTP can make TSH rise while serotonin depletion makes TSH fall. Chen HJ, Meites J. Endocrinology, 1975;Vol 96, 10-14. • Increases in serotonin are paralleled by increases in TSH. Karamouzis M, et al. Hell J Nucl Med. 1999;2:125-30.

21. Serotonin and Thyroid • Giving T3 induces a rise in serotonin • In animals with hypothyroidism, serotonin synthesis is reduced • Sintzel F, et al. Encephale. 2004 May-Jun;30(3):267-75. • Proposed mechanism of action: T3 desensitizes presynaptic serotonin autoreceptors • Bauer M, et al. Mol Psychiatry. 2002;7(2):140-56.

22. Serotonin and Thyroid • Optimal thyroid function, beyond simply being within the normal laboratory values, may be necessary for an optimal response to antidepressants. • Gitlin M, et al. J Psychiatry Neurosci 2004;29(5):383-6. • The thyroid hormone, triiodothyronine (T3), augments and accelerates the effects of antidepressant drugs. • Fluoxetine + T3 better at desensitizing 5-HT hypothalamic autoreceptors than either alone. • Lifschytz T, et al. J Neurosci Methods. 2004 Dec 30;140(1-2):133-9.

23. Serotonin and Thyroid Thyroid function and Serotonin function are Interdependent both clinically andbio-chemically • Optimal thyroid function is dependent on optimal serotonin balance • Optimal serotonin balance is dependent on optimal thyroid function • TSH increase bio-chemically is dependent on adequate serotonin stimulation of hypothalamic TRH allowing TSH to rise

24. Excess Cortisol & Serotonin Excess Cortisol has an inhibitory effect on serotonin function via at least 4 known mechanisms: 1. “Corticosterone treatment was found to induce a …. functional desensitization of somatodendritic 5-HT(1A) autoreceptors.” Leitch MM, et al. Neuropsychopharmacology. 2004 Jan;28(1):119-25. 2. Corticosterone treatment significantly decreased the number of 5-HT1A receptor sites . . . Crayton JW, et al. Brain Res. 1996 Jul 29;728(2):260-2.

25. Excess Cortisol & Serotonin 3. “Cortisol at the nM-microM concentration range induces a substantial increase in serotonin uptake both in vitro …and in vivo, …owing to promotion of synthesis of the serotonin transporter”. Tafet GE, Toister-Achituv M, Shinitzky M. Cogn Affect BehavNeurosci. 2001;1(1):96-104. 4. “Transcription of the gene coding for tryptophan oxygenase (TO) in rat liver is induced 10-fold by glucocorticoids” NOTE: 5-HTP bypasses the TO enzyme and thus can raise serotonin even in the face of excess cortisol Danesch U, et al. EMBO J. 1987 Mar;6(3):625-30.

26. Low Cortisol and Serotonin “[In the amygdala], if endogenous cortisol is removed, 5-HT no longer has an inhibitory effect on glutamatergic activity, suggesting that this hormone (Cortisol)plays a key role in maintaining serotonergic-mediated modulation”. Stutzmann GE, McEwen BS, LeDoux JE. J Neurosci. 1998 Nov.15;18(22):9529-38.

27. Neurotransmitter Pathways“GABA” To highlight the importance of glutamate apart from excitation, it is converted to the physiologically active amine, g-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain.

28. GABA • Gamma-Aminobutyric Acid • Discovered in 1950, most important and widespread inhibitory NT in the brain • Glutamate receptors located on dendrites • GABA receptors located on the cell body • Excitatory signals from the dendritic glutamate receptors must pass through the cell body to the presynaptic terminal • GABA allows only the most important excitatory signals to pass by

29. Panic attack

30. GABA • Too much excitation without adequate GABA inhibition can lead to: • Insomnia • Restlessness • Irritability • Anxiety • Panic Attacks • Seizures • GABA induces relaxation, calmness, aid sleep • Theanine, Lactium (milk peptides), taurine, inositol, and oral bio-identical progesterone can act as nutraceutical GABA agonists • Barbiturates, benzodiazepines and alcohol (dose related) act as GABA agonists

31. Alterations in the gamma-aminobutyric acid (GABA) receptor complex and GABA neurotransmission influence the reinforcing and intoxicating effects of alcohol and benzodiazepines. Withdrawal symptoms stem in part from a decreased GABAergic inhibitory function and an increase in glutamatergic excitatory function. Malcolm RJ.GABA systems, benzodiazepines, and substance dependence.J Clin Psychiatry. 2003;64 Suppl 3:36-40.

32. Glutamate • Primary excitatory neurotransmitter • Synthesized from glutamine or glucose • Glutamate receptors (e.g., NMDA) subject to excitotoxicity

33. Niciu, MJ. Kelmendi, B., et al. Overview of Glutamatergic Neurotransmission in the Nervous System. Pharmacol Biochem Behav. 100(4):656-664. 2012.

34. Glutamate • Excitotoxicity = Neuron Damage/Death • MSG, aspartame play a role in excess glutamate excitotoxicity • Glutamate also seems necessary for TSH to rise. Glutamate also causes a rise in thyroid hormones • Alfonso M, Duran R, Arufe MC. Effect of excitatory amino acids on serum TSH and thyroid hormone levels in freely moving rats. Horm Res. 2000;54(2):78-83.

35. Neurotransmitter Pathways“The CATS” Abbreviations: TH = tyrosine hydroxylase, DHPR = dihydropteridine reductase, H2B = dihydrobiopterin, H4B = tetrahyrobiopterin, MAO = monoamine oxidase, COMT = catecholamine-O-methyltransferase, MHPG = 3-methoxy-4-hydroxyphenylglycol, DOPAC = dihydroxyphenylacetic acid.

36. CATs in balance

37. The “CATS” • The catecholamines are a family of neurotransmitters derived from the amino acids: phenylalanine and/or tyrosine • Dopamine, norepinephrine (Noradrenaline) and epinephrine (Adrenaline) • Synthesis of the “CATS” occurs in : CNS, adrenal medulla, Peripheral Sympathetic Neurons

38. The “CATS” • Norepi and dopamine act primarily as neurotransmitters in the CNS • Epinephrine acts primarily as an adrenal hormone peripherally • The “CATS” are excitatory mediators of the sympathetic autonomic nervous system

39. Dopamine • Dopamine is a catecholamine precursor for norepinephrine and is found both in the CNS and adrenal medulla wherever norepi is found • Diverse functions include: • Motor function and posture • Cognitive function: attention, focus, working memory and problem solving • Motivation for reward • Neuromodulator: can act either as an Inhibitory or Excitatory NT in response to incoming afferent signals

40. Dopamine = Experience of Reward Low Dopamine = Low Pleasure = Anhedonia

41. Serotonin/Norepinephrine & Dopamine • Bio-chemically and clinically, there is often an inverse relationship between: Norepinephrine and/or dopamine (excitatory) & serotonin (inhibitory) • When serotonin is low, norepinephrine may be over-expressed, resulting in “fight or flight” responses leading to anxiety and panic attacks • When serotonin is low, dopamine may be over-expressed resulting in delusional thinking, hypo-manic/ bipolar disorder or even frank psychosis

42. Dopamine Inhibition • Serotonin 2C receptor modulates the activity of mesencephalic dopamine neurons, the dysfunction of which is involved in devastating diseases such as schizophrenia, Parkinson's disease, and drug addiction. De Deurwaerdere P, et al. J Neurosci. 2004 Mar 31;24(13):3235-41. • SSRI’s shown to increase the dopamine transporter in vivo, thereby reducing dopamine function. Kugaya A, et al. Neuropsychopharmacology. 2003 Feb;28(2):413-20.

43. Norepinephrine • Peripheral Sympathetic Nervous system norepinephrine mediates: • The body’s “fight or flight” stress response • Norepinephrine firing is kept under control by GABA inhibition • CNS norepinephrine mediates: • Mood regulation, sleep dysregulation, drive, ambition, learning and memory, alertness and arousal and focus

44. Norepinephrine • Over-expression of CNS norepinephrine clinically associated with: • Anxiety, Aggression, Irritability, Mania or Bipolar Disease, Immune Suppression, Hypertension and CHF • Low Norepinephrine associated with “Atypical Depression” with symptoms of: • Fatigue, Hypersomnia, Hyperphagia, Lethargy and Apathy 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):254-75.

45. Atypical Depression

46. Validity as a Clinical Tool Recently released publication on the Validity of Urinary Neurotransmitter Testing with Clinical Applications of the CSM™ (Communication System Management) Model 22-page document with 117 references from the medical literature

48. Adrenal Fatigue & NT Balance • “Adrenal Fatigue”, with cortisol and DHEA depletion, can lead to a low epinephrine level and elevated Norepi/Epi ratio • Adequate cortisol is needed for the precursor NE to be converted to epinephrine SAMe Norepinephrine cortisol Epinephrine Zuckerman-Levin, et al. The importance of adrenocortical glucocorticoids for adrenomedullary and physiological response to stress: a study in isolated glucocorticoid deficiency. J Clin Endocrinol Metab. 2001 Dec;86(12):5920-4.

49. Epinephrine • Can functions both as a neurotransmitter and a hormone, but clinically primarily acts as a hormone • Derived from precursor norepinephrine in a Cortisol and SAMe - dependent step • CNS NT functions are not well-studied; • Blood pressure control, increased energy and “rush” associated with Methamphetamine blockage of epinephrine re-uptake • Major peripheral Adrenal Hormone mediating Acute Stress Responses

50. Epinephrine • Profound affect on metabolism: catabolic hormone breaking down body stores of fuel for perceived emergencies • Upregulates every system that can contribute to “fight or flight” responses: • Increased heart rate, metabolic rate, glucagon, sodium retention and elevated BP • Dilates bronchii, pupils, small arteries in muscles • Raises blood glucose via gluconeogenesis/glycogenolysis • Chronic stress-mediated over-activation of Epi can lead to Insulin Resistance Brunner EJ, Hemingway H, Walker BR, et al. Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study. Circulation. 2002 Nov 19;106(21):2659-65.