Presentation on theme: "Understanding the HPA-T Axis with Relation to Hormone Imbalance"— Presentation transcript:
1Understanding the HPA-T Axis with Relation to Hormone Imbalance R.W. Watkins, MD, MPH, FAAFPSanesco Roundtable4 May 2013Charlotte, NC
2Introductions R.W. “Chip” Watkins, MD, MPH, FAAFP Past-President and Board Chair – NCAFPAssoc Prof of Family Medicine – UNC, ECUChief Medical Officer, Sanesco InternationalPresident/Lab Director, NeuroLab, Inc.President/CEO, NCHealthSPAN, Inc.Former Medical Director, Genova Dx and Great Smokies Diagnostic Lab, Asheville, NC
5Learning ObjectivesDevelop an overview of the interconnectedness of the neuroendocrine communication systemIdentify the major neurotransmitters and their functionUnderstand the balance between inhibitory and excitatory neurotransmitters and their relationship to hormonal imbalances such as PMS and menopausal symptomsWhat is the neuroendocrine system? It is a integrated, functional, and balanced system that includes the CNS, autonomic nervous system and the enteric nervous system. It also includes the endocrine hormonal systems and the immune system modulators – the eicosonoids and the cytokines, etc. It is our biochemical cross-talk system.
6Overview Neurotransmitters Hormones Thyroid hormonesAdrenal hormonesSex hormonesUnderstanding the inter-relationships between them
7Neuronal PathwaysOptimal function dependent upon balanced NT release and reuptake in the synapseNT release must be adequate or the communication cannot continueImbalance of the Neuro-immuno-endocrine Communication System can lead to many pro-inflammatory degenerative diseasesImbalance in the Communication System can contribute to hormonal imbalancesAdaptation of CNS – more we ask it to do something, the more likely we are going to react in the same way next time. Ex: seizures.
9Natural Hormones: Evaluation for NT-HRT H & P and laboratoryCBCSMAC 20 with lipidsTSH, fT3 , fT4, rT3Thyroid auto-antibodiesEstradiol (E2), ProgesteroneFree & Total TestosteroneDHEA-SPregnenoloneFSH, LHSHBG (Sex Hormone Binding Globulin)TBG (Thyroid Binding Globulin)DHT (Dihydrotestosterone)2:16 Estrogen Metabolite RatioIodine levels (24 hr. urine)MammographyPap SmearDEXA scan of hip and spinePSA (males)Prolactin (if indicated)Sonography (if indicated)Intracellular minerals3-Hour GITT: Insulin Resistance TestNeurotransmitter levels (spot urine sample)AI: Adrenal Index (saliva)Test in luteal phase, if still menstruating
10Common Neurotransmitters SerotoninGABAGlutamateDopamineNorepinephrineEpinephrineThese top “BIG 6” are measured initially to assess a person’s neurotransmitter balanceWill be adding glycine and histamine shortly
13How can I use this information? Initial Assessment of patientWhat is the current state of their nervous and hormonal systems?Helps you guide therapyIs patient on SSRI or SNRI?Other medications that can effect NTs?Helps you monitor patient progressHelps you maintain patient improvements
14Early 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 anxietyIncreased understanding of Biochemical PathwaysAmino Acids precursors to NeurotransmittersAmino Acid TherapyPharmaceutical research suggested drug-based mechanisms for neuromodulationSSRI’s (Prozac 1987)SNRI’s. (Wellbutrin 1989, etc.)Research began in the 1960’s-1980’s suggested that repletion of the Big 6 NT’s, especially Serotonin, was found to improve mood disorders, particularly depression and anxiety
16Neurotransmitter Balancing “Filling the Tank” Only amino acid precursors are able to replete NT reservesSSRI’s/SNRI’s do not “fill the tank” but rather improve NT function by slowing NT reuptakeAppropriately balancing hormones will make NT’s work more efficaciouslyOnly amino acid precursors are able to replete NT reserves and “fill up the tank” – where do these come from? FOOD!SSRI’s/SNRI’s do not “fill the tank” but rather improve NT function by slowing NT reuptake - “improving gas mileage”Appropriately balancing hormones makes NT’s work more efficaciously – “improving performance”
17Neurotransmitter Pathways “Serotonin” This is the pathway that seems to be modulating the other NT imbalances as the most direct relationship with hormones.Seem to be having the most trouble with depletion due to stress, blood sugar issues, aging, and the environmentPathway 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
18Serotonin 5-HT or 5-hydroxytryptamine 1-2% in CNS95% in gut enteric nervous system2-3% in platelets5-HT acts as an inhibitory neurotransmitter5-HT acts as a neuromodulatorAffects glutamate excitability over diverse regions of the CNSActs by stimulating its own receptors on GABA neurons prompting GABA to perform its inhibitory functionActs to inhibit the release of the catecholamines (“CATS”): dopamine, NE, epinephrineArea of lots of research and new drugs.Doesn’t have a lot of action on its own. Most have adequate GABA. 5HT low – cats go high. When 5HT high, cats come down – cooling off the system. It doesn’t make sense to just give a drug to stimulate GABA receptors and quash NE effects – it makes much more sense to me to bring up the inhibitory side and allow the body to balance things out.
195-HTP has been used clinically for over 30 years 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.This is an EXCELLENT review article on 5-HTP and everything related to it. I have also included another reference for your review from Alt Med Rev – another great review article.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.
20Serotonin and ThyroidDiurnal TSH peak found to be serotonin-dependent.Jordan D, et al. Endocrinology 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,Increases in serotonin are paralleled by increases in TSH.Karamouzis M, et al. Hell J Nucl Med. 1999;2:You start balancing NTs, you will see your hormones working more efficiently. I have had to reduce the dose of thyroid medication in 2 women recently.
21Serotonin and Thyroid Giving T3 induces a rise in serotonin In animals with hypothyroidism, serotonin synthesis is reducedSintzel F, et al. Encephale May-Jun;30(3):Proposed mechanism of action: T3 desensitizes presynaptic serotonin autoreceptorsBauer M, et al. Mol Psychiatry. 2002;7(2):
22Serotonin and ThyroidOptimal 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 Dec 30;140(1-2):133-9.
23Serotonin and ThyroidThyroid function and Serotonin function are Interdependent both clinically and bio-chemicallyOptimal thyroid function is dependent on optimal serotonin balanceOptimal serotonin balance is dependent onoptimal thyroid functionTSH increase bio-chemically is dependent on adequate serotonin stimulation of hypothalamic TRH allowing TSH to rise
24Excess 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):2. Corticosterone treatment significantly decreased the number of 5-HT1A receptor sites . . .Crayton JW, et al. Brain Res Jul 29;728(2):260-2.Cortisol suppresses Serotonin. . . Corticosterone treatment was found to induce a significant attenuation in the response to 8-OHDPAT, indicating desensitization of somatodendritic 5-HT(1A) autoreceptors and thus effects their functioning.2. Excess Cortisol: Fewer Receptor Sites
25Excess 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):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 cortisolDanesch U, et al. EMBO J Mar;6(3):2. Cortisol upregulates Serotonin Transporter3. Excess Cortisol and TO - [TO metabolizes Tryptophan to kynurenin, leaving less Tryptophan to become Serotonin]
26Low 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):
27Neurotransmitter Pathways “GABA” So the first inhibitory NT we talked about was serotonin. GABA is the other main inhibitory NT. Remember this is a balance in the pathway for the major excitatory NT Glutamate and the major inhibitory NT 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.
28GABA Gamma-Aminobutyric Acid Discovered in 1950, most important and widespread inhibitory NT in the brainGlutamate receptors located on dendritesGABA receptors located on the cell bodyExcitatory signals from the dendritic glutamate receptors must pass through the cell body to the presynaptic terminalGABA allows only the most important excitatory signals to pass byWhere there are glutamate receptors (powerful excitatory neurons), there will be GABA receptors nearby. This is really pretty amazing. We are truly built for balance.GABA allows…it is the filter by which you prevent overexcitation of the neurons.
30GABA Too much excitation without adequate GABA inhibition can lead to: InsomniaRestlessnessIrritabilityAnxietyPanic AttacksSeizuresGABA induces relaxation, calmness, aid sleepTheanine, Lactium (milk peptides), taurine, inositol, and oral bio-identical progesterone can act as nutraceutical GABA agonistsBarbiturates, benzodiazepines and alcohol (dose related) act as GABA agonistsGABA keeps us in our skin. As a matter of fact, there are GABA receptors on the hypothalamus that regulate TRH release. GABA inhibits thyroid by being a safety net for the body. If there is too much excitation, GABA acts on the thyroid so the body will not burn itself out.Theanine, etc. brings calm without making us tired. Progesterone and its metabolite allopregnenolone. These are very effective but remember you must balance Serotonin.
31Alterations 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.Evidence suggests that long-term alcohol use and concomitant serial withdrawals permanently alter GABAergic function, down-regulate benzodiazepine binding sites, and in preclinical models lead to cell death.Malcolm RJ.GABA systems, benzodiazepines, and substance dependence. J Clin Psychiatry. 2003;64 Suppl 3:36-40.
32Glutamate Primary excitatory neurotransmitter Synthesized from glutamine or glucoseGlutamate receptors (e.g., NMDA) subject to excitotoxicityThe NMDA receptors (one of the three Glutamate receptors) are subject to neurotoxicity. One of our new drugs for AD is Namenda – works on the NMDA receptors by blocking the accumulation of glutamate and its effect on the brain. But again, perhaps a better way might be instead of blocking glutamate, we would bring up the inhibitory NTs and cool down this neurotoxic systemNot just elevated glutamate, but in relation to the lowered levels of inhibitory NT serotonin and GABA along with imbalances in the hormonesMSG, aspartame – break down and increase levels of glutamate
33Niciu, MJ. Kelmendi, B. , et al Niciu, MJ. Kelmendi, B., et al. Overview of Glutamatergic Neurotransmission in the Nervous System. Pharmacol Biochem Behav. 100(4):Excellent review article – everything you might want to know about glutamate and its receptors.
34Glutamate Excitotoxicity = Neuron Damage/Death MSG, aspartame play a role in excess glutamate excitotoxicityGlutamate also seems necessary for TSH to rise. Glutamate also causes a rise in thyroid hormonesAlfonso 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.So there is a balance here as well. But this does show the importance of EAAs in the regulation of hormone secretion from the HPAT axis, as well as the importance of the NMDA and non-NMDA receptors in this stimulatory effect.
35Neurotransmitter Pathways “The CATS” Metabolism of the catecholamine neurotransmitters. Only clinically important enzymes are included in this diagram. The catabolic byproducts of the catecholamines, whose levels in the cerebrospinal fluid are indicative of defects in catabolism, are underlined.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.
37The “CATS”The catecholamines are a family of neurotransmitters derived from the amino acids: phenylalanine and/or tyrosineDopamine, norepinephrine (Noradrenaline) and epinephrine (Adrenaline)Synthesis of the “CATS” occurs in : CNS, adrenal medulla, Peripheral Sympathetic Neurons
38The “CATS”Norepi and dopamine act primarily as neurotransmitters in the CNSEpinephrine acts primarily as an adrenal hormone peripherallyThe “CATS” are excitatory mediators of the sympathetic autonomic nervous systemBoth are NT, NE functions primarily as a neurotransmitter. Epi functions mostly as a adrenal hormone. NE works more on perception in the brain, and epi more the fight or flight in the body.Sympathetic NS is not a bad system – it is crucial for our survival, but when things become imbalanced and we are stuck in this sympathetic overdrive, we start to have problems.
39DopamineDopamine is a catecholamine precursor for norepinephrine and is found both in the CNS and adrenal medulla wherever norepi is foundDiverse functions include:Motor function and postureCognitive function: attention, focus, working memory and problem solvingMotivation for rewardNeuromodulator: can act either as an Inhibitory or Excitatory NT in response to incoming afferent signalsWe all know this from Parkinson’s – the disease where dopamine is most studied. PD is a neurodegenerative disease of low dopamine causing neuro-motor disruption.Feel good NT – what people are going for with their additions. Most interesting NT and one we understand the least
40Dopamine = Experience of Reward Low Dopamine = Low Pleasure =AnhedoniaRemember Woody Allen & Annie Hall?Anhedonia – could call it lack of dopamine
41Serotonin/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 attacksWhen serotonin is low, dopamine may be over-expressed resulting in delusional thinking, hypo-manic/ bipolar disorder or even frank psychosis
42Dopamine InhibitionSerotonin 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):SSRI’s shown to increase the dopamine transporter in vivo, thereby reducing dopamine function.Kugaya A, et al. Neuropsychopharmacology Feb;28(2):If you ever see PD patients that are on a lot of sinemet or stelevo or other dopamine enhancing drugs, you will find sky high dopamine levels and low serotonins. These people need to have their serotonin balanced.
43NorepinephrinePeripheral Sympathetic Nervous system norepinephrine mediates:The body’s “fight or flight” stress responseNorepinephrine firing is kept under control by GABA inhibitionCNS norepinephrine mediates:Mood regulation, sleep dysregulation, drive, ambition, learning and memory, alertness and arousal and focusNE works more in the brain as a NT and deals with the perception of fight or flight whereas epinephrine works more in the body as a hormone for blood pressure control and heart rate increaseGABA works in concert with serotonin for control of NE levels. Need enough NE for mood regulation…vegetative depressions often have less NE (extreme fatigue, sleeping too much, eating too much, apathy) – which effexor, cymbalta and nutriceuticals can be used to help here.
44NorepinephrineOver-expression of CNS norepinephrine clinically associated with:Anxiety, Aggression, Irritability, Mania or Bipolar Disease, Immune Suppression, Hypertension and CHFLow Norepinephrine associated with “Atypical Depression” with symptoms of:Fatigue, Hypersomnia, Hyperphagia, Lethargy and ApathyGold 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):
46Validity as a Clinical Tool Recently released publicationon theValidity of Urinary NeurotransmitterTestingwith Clinical Applications ofthe CSM™ (CommunicationSystem Management) Model22-page document with117 references from the medicalliterature
48Adrenal Fatigue & NT Balance “Adrenal Fatigue”, with cortisol and DHEA depletion, can lead to a low epinephrine level and elevated Norepi/Epi ratioAdequate cortisol is needed for the precursor NE to be converted to epinephrineSAMeNorepinephrine cortisol EpinephrineZuckerman-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):Epi acts as a neurotransmitter but primarily as an adrenal hormone responsible for fight or flight. Epi is a fairly good representation of adrenal function and often see…NE again more involved in the perception of stress and activation of the sympathetic autonomic nervous system overactivationLooks like exogenous cortisol does not help in this step, but endogenous does
49EpinephrineCan functions both as a neurotransmitter and a hormone, but clinically primarily acts as a hormoneDerived from precursor norepinephrine in a Cortisol and SAMe - dependent stepCNS NT functions are not well-studied;Blood pressure control, increased energy and “rush” associated with Methamphetamine blockage of epinephrine re-uptakeMajor peripheral Adrenal Hormone mediating Acute Stress ResponsesCNS is not where the action is with epi – works more in the periphery –blood pressure control, heart rate. Methamphetamine is a high epi state until they burn out – too much epi = fight or flight, HBP, fast pulse, sweating, etc.
50EpinephrineProfound affect on metabolism: catabolic hormone breaking down body stores of fuel for perceived emergenciesUpregulates every system that can contribute to “fight or flight” responses:Increased heart rate, metabolic rate, glucagon, sodium retention and elevated BPDilates bronchii, pupils, small arteries in musclesRaises blood glucose via gluconeogenesis/glycogenolysisChronic stress-mediated over-activation of Epi can lead to Insulin ResistanceBrunner 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):Very important function for us, if we are in the jungle and getting chased by the tiger, we want a lot of epinephrine to mobilize fuel, get our blood clotting, raise our heart rate and blood pressure, heighten our senses, etc. But it is the CHRONIC PERCEPTION of the tiger chasing us that is the problem in our modern society. Don’t want this system running full bore all the time.Dilates… so we can RUN from the tiger
52Epinephrine 3 phases of stress response Phase I: Alarm reaction: Hi Epi/Hi CortisolPhase II: Resistance: Hi Cortisol/Low DHEAEpi variablePhase III: Exhaustion: Depletion of Cortisol, Epi, DHEAMost patients presenting tomy office are in theresistance/exhaustion phaseof adrenal adaptationDr. Hans Selye “General Adaptation Syndrome” (Selye, 1978)GAS is what is effecting adrenal function and adrenal function is tied to the catecholamines in the brain.Tiger chasing – or someone cuts you off in traffic. Not a good thing to have this system up regulated all the time. “Why Zebras don’t get ulcers”DHEA most abundant hormone in the body. DHEA goes down when epi chronically up.III. This is where most of my patients show up.
53DHEA: A Central Neuroactive Steroid The most abundant adrenal hormone produced in the zona reticularis of the adrenal cortexDHEA/S is synthesized from pregnenolone under the influence of pituitary ACTHPrecursor to both estrogen & testosterone especially important after menopause and andropauseAnti-Stress role physiologically to balance & modulate the effects of excess cortisolAdrenopause: Age related decline in function of the adrenal cortex characterized by: (age onset )↓↓ DHEA/S & Cortisol
54Changes in serum DHEA-S (DHEA Sulfate) level with age (Redrawn from Finch and Mobbs, 1982)
55DHEA: Biomarker for Aging? May Help Prevent or Treat:Cardiovascular DiseaseElevated CholesterolDiabetesCognitive Disorders/Alzheimer’sAllergic DisordersOsteoporosisImmune Dysregulation:CFIDS, HIV, SLE (Lupus)Cancer preventionIn men, a number of studies have shown that DHEA-S levels are significantly lower in men with a history of CAD than in men without CAD. The effect is modest however. The effect appears to be opposite in women.I have had a number of patients who have responded nicely to DHEA administration with regard to their allergies and chemical sensitivities.Osteoporosis – DHEA may be essential for maintenance of bone mass in post-menopausal women – one of DHEA’s metabolites binds strongly to estrogen receptors, androgens stimulate bone growth and calcium absorption, DHEA is partially converted to estrogens.
56DHEA & Neurotransmitters Inhibits GABA; is a GABA antagonistShen W, et al. Neuropharmacology Feb;38(2):Increases dopamine & norepinephrine synthesis via mRNA for tyrosine hydroxylaseCharalampopoulos I, et al. Endocrinology Aug;146(8):Increases firing activity of serotonin neuronsRobichaud M, Debonnel G. J Endocrinol Jul;182(1):11-21.
57DHEA 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):
58DHEA - Safety1600 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):200mg/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 dosesMonitor levelsLong-term effects are unknownCaution in those with history or family history of hormone related cancersKeep levels on the lower end of range. What for thyroid levels – will get sx in about 10%.
59DHEA Quick SummaryImpacts neurotransmitters: both excitatory and inhibitoryServes as neuroprotection to CNS hippocampal neuronsAnti-stress role as antagonist to cortisol
60Transitional Years 35 years – anovulation - progesterone Anxiety, loosing sleep - GABA45 years - estrogen - serotoninFatigueInsomniaMigrainesHot flashes/vasomotor instabilityDecreased brain function/memory issuesDepression/Anxiety/Emotional volatilityI think this is much higher in the transitional years of perimenopause, menopause, and andropause. You see this in women starting around 35 when they start to have anovulatory periods, loosing progesterone, they can’t sleep, they are anxious, they are dropping their GABA. A little later in their 40s when estrogen levels start to rock and roll, and then start declining, they are dropping their serotonin. The greatest complaints, fatigue, insomnia, migraines, hot flashes, vasomotor instability, decreased brain function, anxiety, depression, emotional volitility, forgetfulness, memory issues. This is the impact of the waning of the hormones on a brain that was already low in NTs. If you correct and balance both of these, they will well quickly and stay well.Bio-chemically the hormone-producing glands are enervated by nerve cellsThese glands do not function on their own but await communication from the nerves that serve themReceptors for many neurotransmitters are located on the hypothalamus
61CHANGE “BITCHY” TO “WITCHY” AND “PSYCHO” TO “MOODY”?
62Estrogen 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 Nature’s SSRI in womenKoldzic-Zivanovic N, et al. Mol Cell Endocrinol Oct 29;26(1-2):33-42.
63Estrogen’s effect on Dopamine Estrogen seems to exert a potent protective effect that maintains the integrity of the nigral dopamine systemEstrogen inhibits the release of dopamine in the brain and prolongs the uptake of excess dopamine from the synapseEstrogen’s 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):
64Laboratory Results of Estrogen Dominance Elevated SHBGBinds up Free Testosterone + de-activates itElevated TBG, Thyroid Binding GlobulinDecreases thyroid functionThyroid hormone needed for optimum estrogen metabolismDecreased thyroid function worsens estrogen dominanceIncreased Aromatase EnzymeConverts testosterone to estrone via androstenedione pathwayFurther perpetuates estrogen dominanceIncreased Interleukin – 6 (Cytokine Imbalance)Increases insulin resistance which further enlarges abdominal fat pad thus producing more estrone and worsening estrogen dominance
65Estrogen’s Effect on Neurotransmission Women are twice as likely to suffer from mood disorders as menA growing body of evidence points to estrogen’s importance in serotonergic and dopaminergic function.We have already looked at estrogen’s effect on serotonin and dopamine
66Use 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.
67Using 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 necessaryHaliloglu 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.Whether that be with hormones, herbals, or SSRIs, etc.
68PMS and PMDDPMDD can be distinguished from PMS by the severity of symptoms and the predominance of mood symptomsSelective serotonin reuptake inhibitors (SSRIs) have emerged as first-line therapySeveral strategies have evolved in the literature:SSRIs can be administered continuously throughout the entire monthSSRIs can be used intermittently from ovulation to the onset of menstruationOr they can be used semi-intermittently with dosage increases during the late luteal phaseWyatt KM, Dimmock PW, O'Brien PM. Selective serotonin reuptake inhibitors for premenstrual syndrome. Cochrane Database Syst Rev. 2002;(4):CDThe principle features of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) are the predictable, cyclic nature of symptoms that often begin in the late luteal phase of the menstrual cycle and usually remit shortly after the onset of menstruation.PMDD - particularly regarding the areas of personal relationships and the marital/family dynamic.
69PMS and PMDDUsing 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(many of whom have been on SSRIs for their prior treatment)Not infrequently, patients with severe symptoms must remain on some level of medication to help manage their symptoms, but almost universally, they are managed with less medication and the medication they use is much more effective.
71Essential Information About Progesterone Increased stress contributes to progesterone deficiency — progesterone converted to cortisolCortisol competes for progesterone receptors and helps to produce effects of progesterone deficiencyThus, stress of all kinds may lead to progesterone deficiency and contribute to estrogen dominance
72Progesterone & GABAAllopregnanolone 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 GABAA 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.
74Symptoms and Signs of Androgen Deficiency in Women Vaginal drynessThinning SkinBone LossAches/painsUrinary IncontinenceDecreased Muscle MassIncreased Fat depotDepressionLack of assertivenessMemory Lapses“Brain Fog”Sleep DisturbancesLow libidoFatigueLack of vigor/focusI recently had a patient come in and she was complaining about all these issues. She came back to go over her test results and I informed her that her testosterone was really low. She said, “Yeah, my GYN told me my testosterone was really low a couple of years ago when I told him I had no libido. I asked “did he give you any testosterone?” She said, No. I told her obviously he never had a wife with low testosterone!”
75Natural TestosteroneGive in morning, preferably to correlate with diurnal secretionCommon Dosage range:WomenMenOral:1-10 mg/dayUsually 2-5mg/daymg/dayUsually 35-50mg/dSublingual:0.625mg–5 mg/day10 mg – 35mg/dayTransdermal:0.5 – 8 mg/day10mg – 50 mg/day
76Testosterone 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):
78Hormone Effects on NT’s Estrogen: serotonin agonist, dopamine modulatorProgesterone: GABA agonistTestosterone: serotonin agonist, dopamine agonistDHEA: dopamine, NE, serotonin agonist, GABA antagonistNeuro-protective, Neuronal plasticityThyroid: serotonin agonistCortisol excess: blocks serotonin and tryptophan metabolism into serotonin; use 5-HTP to bypassCortisol deficiency: serotonin, epinephrine norepinephrine, glutamateInsulin excess (Insulin Res.): serotonin,NE, dopamineHormones have varied effects on neurotransmission. Neurons have surface receptors for hormones that can facilitate depoloarization. Estradiol, the best studied, can increase the synthesis of serotonin and inhibit the MAO mediated breakdown of NTs. Estradiol is a serotonin agonist and can slow the uptake of the other neurotransmitters.We all know how many of the hormones effect the body, but what is exciting about this information for me has been looking at hormones and neurotransmission and how affects the patients brain. We can give patients their lives back. It is so much fun.We see so much overweight and insulin resistance. If you don’t raise serotonin, and tell them to cut carbs and go on an insulin-sparing diet, they are not going to be able to stick to program. Carbs raise serotonin (feel good food) and then serotonin follows glucose into the cell. And if they are not sleeping, they have no energy to participate in a healthy lifestyle. When we restore balance, they will find their path.
79NT Effects on Hormones Serotonin: thyroid function Necessary to TSH appropriately for feedback loop stimulation of fT3 and fT4Adrenal support; cortisol appropriatelyGABA: Inhibits thyroid functionDopamine: Prolactin, Growth HormoneNE excess: Acute: CortisolChronic: CortisolEpinephrine excess: Insulin Resistance - InsulinHPAT balance: Hormone producing glands are innervated by nerve cells. The glands do not function on their own, but await for communication from the nerves that serve them. NT receptors are located on the hypothalamus. This is ONE interactive system.NT can increase production of hormones from the pituitary. Studies show that Serotonin can increase the synthesis of hormones from the anterior pituitary – including ACTH – which restores adrenal function. If you raise serotonin, the NE comes down with the fight or flight comes down, adrenal epi normalizes and you can balance the adrenal system this way.
80Neuro-Endocrine Balance An imbalance in any one aspect of NT or hormone system leads to a compensatory imbalance of both systemsImbalance perpetuates imbalanceRe-establishment of optimal balance IS possibleAssessment is accomplished through serum and saliva hormone levels and urinary levels of NTs, along with clinical improvements.This is an incredibly complex and intricate web of interactions starting in the brain in the limbic system. There are receptors for hormones and NT on the hypothalamus that orchestrate this whole system. Signals then go to the pituitary, again where there are receptors for hormones and NTs. Imbalances are almost always multifactorial. There is incredible sophistication along the HPAT axis. This is just an introduction. But for my money, it is the only game in town. This is where the rubber meets the road on so many levels. If we can begin to balance this system we can get real quality of life for our patients and give them their lives back – many of them – and prevent, I believe, much chronic disease.You can balance the hormones, but adding the NTs gives a whole new level of precision to what you are doing.Balance is possible. Bioidentical hormones, amino acid precursors, vitamins, minerals, essential fats (list them out) and if we need to we can add the SSRI and SNRIs or other medications, but bringing balance to the system we will be able to use many times less medication or what we use will work better. We can check our spot NTs, salivary cortisols and DHEA-S. Make an intervention, and reassessPatients get well, they stay well, they loose weight, and I think we are doing the best we can do with our patients. Doing these tests has really changed my practice in a really positive way.
81We can positively affect how women and men transition through Life It’s All About Balance