Presentation on theme: "Understanding the HPA-T Axis with Relation to Hormone Imbalance R.W. Watkins, MD, MPH, FAAFP Sanesco Roundtable Sanesco Roundtable 4 May 2013 Charlotte,"— Presentation transcript:
Understanding the HPA-T Axis with Relation to Hormone Imbalance R.W. Watkins, MD, MPH, FAAFP Sanesco Roundtable Sanesco Roundtable 4 May 2013 Charlotte, NC
Introductions R.W. Chip Watkins, MD, MPH, FAAFP Past-President and Board Chair – NCAFP Assoc Prof of Family Medicine – UNC, ECU Chief Medical Officer, Sanesco International President/Lab Director, NeuroLab, Inc. President/CEO, NCHealthSPAN, Inc. Former Medical Director, Genova Dx and Great Smokies Diagnostic Lab, Asheville, NC
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
Overview Neurotransmitters Hormones Thyroid hormones Adrenal hormones Sex hormones Understanding the inter-relationships between them
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
Neurotransmitters: The tip of the iceberg
Natural Hormones: Evaluation for NT-HRT 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) H & P and laboratory Test in luteal phase, if still menstruating
Common Neurotransmitters Serotonin GABA Glutamate Dopamine Norepinephrine Epinephrine These top BIG 6 are measured initially to assess a persons neurotransmitter balance
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
Early Research on NTs Research began in the 1960s-1980s 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 SSRIs (Prozac 1987) SNRIs. (Wellbutrin 1989, etc.)
Neurotransmitter Balancing Filling the Tank Only amino acid precursors are able to replete NT reserves SSRIs/SNRIs do not fill the tank but rather improve NT function by slowing NT reuptake Appropriately balancing hormones will make NTs work more efficaciously
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
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
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 Mar;109(3): Review. T.C. Birdsall, 5-Hydroxytryptophan: a clinically-effective serotonin precursor, Altern Med Rev 3 (1998), pp. 271–280.
Serotonin and Thyroid Diurnal TSH peak found to be serotonin-dependent. Jordan D, et al. Endocrinology Oct;105(4): Giving 5-HTP can make TSH rise while serotonin depletion makes TSH fall. Chen HJ, Meites J. Endocrinology, 1975;Vol 96, Increases in serotonin are paralleled by increases in TSH. Karamouzis M, et al. Hell J Nucl Med. 1999;2:
Serotonin and Thyroid Giving T3 induces a rise in serotonin In animals with hypothyroidism, serotonin synthesis is reduced Sintzel F, et al. Encephale May-Jun;30(3): Proposed mechanism of action: T3 desensitizes presynaptic serotonin autoreceptors Bauer M, et al. Mol Psychiatry. 2002;7(2):
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): 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 Dec 30;140(1- 2):133-9.
Serotonin and Thyroid Thyroid function and Serotonin function are Interdependent both clinically and bio- 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
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 Jan;28(1): Corticosterone treatment significantly decreased the number of 5-HT1A receptor sites... Crayton JW, et al. Brain Res Jul 29;728(2):260-2.
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 Behav Neurosci. 2001;1(1): 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 Mar;6(3):
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 Nov.15;18(22):
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.
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
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
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.
Glutamate Primary excitatory neurotransmitter Synthesized from glutamine or glucose Glutamate receptors (e.g., NMDA) subject to excitotoxicity
Niciu, MJ. Kelmendi, B., et al. Overview of Glutamatergic Neurotransmission in the Nervous System. Pharmacol Biochem Behav. 100(4):
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.
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
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
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
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
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 Mar 31;24(13): SSRIs shown to increase the dopamine transporter in vivo, thereby reducing dopamine function. Kugaya A, et al. Neuropsychopharmacology Feb;28(2):
Norepinephrine Peripheral Sympathetic Nervous system norepinephrine mediates: The bodys 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
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):
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
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 Dec;86(12):
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
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 Nov 19;106(21):
Epinephrine 3 phases of stress response Phase I: Alarm reaction: Hi Epi/Hi Cortisol Phase II: Resistance: Hi Cortisol/Low DHEA Epi variable Phase III: Exhaustion: Depletion of Cortisol, Epi, DHEA Most patients presenting to my office are in the resistance/exhaustion phase of adrenal adaptation
DHEA: A Central Neuroactive Steroid The most abundant adrenal hormone produced in the zona reticularis of the adrenal cortex DHEA/S is synthesized from pregnenolone under the influence of pituitary ACTH Precursor to both estrogen & testosterone especially important after menopause and andropause Anti-Stress role physiologically to balance & modulate the effects of excess cortisol Adrenopause: Age related decline in function of the adrenal cortex characterized by: (age onset ) DHEA/S & Cortisol
Changes in serum DHEA-S (DHEA Sulfate) level with age (Redrawn from Finch and Mobbs, 1982)
DHEA: Biomarker for Aging? May Help Prevent or Treat: Cardiovascular Disease Elevated Cholesterol Diabetes Cognitive Disorders/Alzheimers Allergic Disorders Osteoporosis Immune Dysregulation: CFIDS, HIV, SLE (Lupus) Cancer prevention
DHEA & Neurotransmitters Inhibits GABA; is a GABA antagonist Shen W, et al. Neuropharmacology Feb;38(2): Increases dopamine & norepinephrine synthesis via mRNA for tyrosine hydroxylase Charalampopoulos I, et al. Endocrinology Aug;146(8): Increases firing activity of serotonin neurons Robichaud M, Debonnel G. J Endocrinol Jul;182(1):11-21.
DHEA Neuro-Protection We have found that DHEA(S) can prevent or reduce the neurotoxic actions in the hippocampus of the glutamate agonists NMDA and AMPA in vitro and in vivo. Decreased DHEA levels may contribute significantly to the increased vulnerability of the aging or stressed human brain to such damage. Kimonides VG, Khatibi NH, Svendsen CN, Sofroniew MV, Herbert J. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc Natl Acad Sci U S A Feb 17;95(4):
DHEA - Safety 1600 mg/d for 28 days in healthy volunteers - no significant SE except for mild insulin resistance. Mortola JF, Yen SS.The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab Sep;71(3): mg/d in SLE studies for 6 months well-tolerated except for mild to moderate acne/hirsutism. van Vollenhoven RF, Engleman EG, An open study of dehydroepiandrosterone in systemic lupus erythematosus. Arthritis Rheum Sep;37(9): DHEA appears to be safe at physiologic doses Monitor levels Long-term effects are unknown Caution in those with history or family history of hormone related cancers
DHEA Quick Summary Impacts neurotransmitters: both excitatory and inhibitory Serves as neuroprotection to CNS hippocampal neurons Anti-stress role as antagonist to cortisol
Transitional Years 35 years – anovulation - progesterone Anxiety, loosing sleep - GABA 45 years - estrogen - serotonin Fatigue Insomnia Migraines Hot flashes/vasomotor instability Decreased brain function/memory issues Depression/Anxiety/Emotional volatility
Estrogen supports Serotonin… Estrogen treatment shown to selectively enhance 5-HT1A-mediated responses in the hippocampus. Clarke WP, Maayani S. Brain Res Jun 4;518(1-2): Estrogen increased the firing activity of 5-HT neurons in both male and female rats. Robichaud M, Debonnel G. J Neuroendocrinol Mar;17(3): Estrogen inhibits serotonin reuptake. It is Natures SSRI in women Koldzic-Zivanovic N, et al. Mol Cell Endocrinol Oct 29;26(1-2):33-42.
Estrogens effect on Dopamine Estrogen seems to exert a potent protective effect that maintains the integrity of the nigral dopamine system Estrogen inhibits the release of dopamine in the brain and prolongs the uptake of excess dopamine from the synapse Estrogens modulation of…This release and uptake of dopamine normalizes the amount of dopamine in the system, keeping the dopamine levels from exhibiting wide fluctuations. Wong M, Thompson TL, Moss RL. Crit Rev Neurobiol. 1996;10(2):
Laboratory Results of Estrogen Dominance Elevated SHBG Binds up Free Testosterone + de-activates it Elevated TBG, Thyroid Binding Globulin Decreases thyroid function Thyroid hormone needed for optimum estrogen metabolism Decreased thyroid function worsens estrogen dominance Increased Aromatase Enzyme Converts testosterone to estrone via androstenedione pathway Further perpetuates estrogen dominance Increased Interleukin – 6 (Cytokine Imbalance) Increases insulin resistance which further enlarges abdominal fat pad thus producing more estrone and worsening estrogen dominance
Estrogens Effect on Neurotransmission Women are twice as likely to suffer from mood disorders as men A growing body of evidence points to estrogens importance in serotonergic and dopaminergic function.
Use of anti-depressants for menopausal symptoms The use of SSRIs and SNRIs as a non-hormonal therapy for hot flushes is well established. These drugs can be used in conjunction with NT support formulas when necessary. Soares CN, Joffe H, Viguera AC. Paroxetine versus placebo for women in midlife after hormone therapy discontinuation. Am J Med Feb;121(2): e1. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA Jun 4;289(21): Speroff L, Gass M, Constantine G, Olivier S. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol Jan;111(1):77-87.
Using NT support as Therapy Estrogen is known to be a powerful, natural SSRI in its own right. When balancing NTs in women with hot flushes, it is very common to have this be the only therapy necessary. Again, NT support can be used with drug therapies when necessary Haliloglu B, Benli Aksungar F, Ilter E, Temelli Akin F. Serotonin dilemma in postmenopausal women: is it low or high? Maturitas Jun 20;60(2): Koldzic-Zivanovic N, Seitz PK, Watson CS, Cunningham KA, Thomas ML. Intracellular signaling involved in estrogen regulation of serotonin reuptake. Mol Cell Endocrinol Oct 29;226(1-2):33-42.
PMS and PMDD PMDD can be distinguished from PMS by the severity of symptoms and the predominance of mood symptoms Selective serotonin reuptake inhibitors (SSRIs) have emerged as first-line therapy Several strategies have evolved in the literature: SSRIs can be administered continuously throughout the entire month SSRIs can be used intermittently from ovulation to the onset of menstruation Or they can be used semi-intermittently with dosage increases during the late luteal phase Wyatt KM, Dimmock PW, O'Brien PM. Selective serotonin reuptake inhibitors for premenstrual syndrome. Cochrane Database Syst Rev. 2002;(4):CD
PMS and PMDD Using the CSM model, many physicians have seen profound improvements in mood and behavior in patients with PMS/PMDD. Typical patient has low serotonin levels and often elevated NE levels as well. As serotonin levels and other inhibitory NTs are improved, we typically see NE levels decrease as the system is brought into balance. Often there will be a luteal phase defect in progesterone as well as low adrenal function
Essential Information About Progesterone Increased stress contributes to progesterone deficiency progesterone converted to cortisol Cortisol competes for progesterone receptors and helps to produce effects of progesterone deficiency Thus, stress of all kinds may lead to progesterone deficiency and contribute to estrogen dominance
Progesterone & GABA Allopregnanolone is synthesized by the reduction of progesterone via the enzymes 5- reductase and 3-hydroxysteroid dehydrogenase (3-HSD). Allopregnanolone is one of the most potent known modulators of GABA A receptors. Marx CE. Psychiatric Times Oct;vol XVIII(10). Allopregnanolone… has behavioral and biochemical characteristics similar to ethanol, barbiturates, and benzodiazepines. Sinnott RS, Mark GP, Finn DA. Pharmacol Biochem Behav Jul;72(4):923-9.
Symptoms and Signs of Androgen Deficiency in Women Vaginal dryness Thinning Skin Bone Loss Aches/pains Urinary Incontinence Decreased Muscle Mass Increased Fat depot Depression Lack of assertiveness Memory Lapses Brain Fog Sleep Disturbances Low libido Fatigue Lack of vigor/focus
Natural Testosterone Give in morning, preferably to correlate with diurnal secretion Common Dosage range: WomenMen Oral: 1-10 mg/day Usually 2-5mg/day mg/day Usually 35-50mg/d Sublingual: 0.625mg–5 mg/day10 mg – 35mg/day Transdermal: 0.5 – 8 mg/day10mg – 50 mg/day
Testosterone Effects Neurotransmission Menopausal women who received both E2 and Testosterone (T) felt more composed, elated, and energetic than those who were given E alone. Sherwin BB. J Affect Disord Mar-Apr;14(2): Testosterone increases serotonergic neuron firing in the raphe area, increasing mood. Robichaud M, Debonnel G. J Neuroendocrinol Mar;17(3): Testosterone increases central nitric oxide synthase; nitric oxide increases dopamine release, necessary for sexual motivation. Hull EM, et al. Physiol Behav Nov 15;83(2):
NT Effects on Hormones Serotonin: thyroid function Necessary to TSH appropriately for feedback loop stimulation of fT3 and fT4 Adrenal support; cortisol appropriately GABA: Inhibits thyroid function Dopamine: Prolactin, Growth Hormone NE excess: Acute: Cortisol Chronic: Cortisol Epinephrine excess: Insulin Resistance - Insulin
Neuro-Endocrine Balance An imbalance in any one aspect of NT or hormone system leads to a compensatory imbalance of both systems Imbalance perpetuates imbalance Re-establishment of optimal balance IS possible Assessment is accomplished through serum and saliva hormone levels and urinary levels of NTs, along with clinical improvements.
We can positively affect how women and men transition through Life Its All About Balance
Do you feel like this??
In Summary … True health is living well, as well as living longer. It is the art of balance and communication within the neuro-endocrine system.
Understanding the HPA-T Axis with Relation to Hormone Imbalance R.W. Watkins, MD, MPH, FAAFP Sanesco Roundtable Sanesco Roundtable 4 May 2013 Charlotte, NC