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Understanding the HPA-T Axis with Relation to Hormone Imbalance

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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, Sanesco International President/Lab Director, NeuroLab, Inc. President/CEO, NCHealthSPAN, Inc. Former Medical Director, Genova Dx and Great Smokies Diagnostic Lab, Asheville, NC

3 Introductions

4 How did I get into this game?

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 What 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.

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 Adaptation 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.

8 Neurotransmitters: The tip of the iceberg

9 Natural Hormones: Evaluation for NT-HRT
H & P and laboratory 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) Test in luteal phase, if still menstruating

10 Common Neurotransmitters
Serotonin GABA Glutamate Dopamine Norepinephrine Epinephrine These top “BIG 6” are measured initially to assess a person’s neurotransmitter balance Will be adding glycine and histamine shortly



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.) 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


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 Only 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”

17 Neurotransmitter 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 environment 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 Area 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.

19 5-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.

20 Serotonin and Thyroid Diurnal 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.

21 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):

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 Dec 30;140(1-2):133-9.

23 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

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 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

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 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 cortisol Danesch U, et al. EMBO J Mar;6(3): 2. Cortisol upregulates Serotonin Transporter 3. Excess Cortisol and TO - [TO metabolizes Tryptophan to kynurenin, leaving less Tryptophan to become Serotonin]

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 Nov.15;18(22):

27 Neurotransmitter 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.

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 Where 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.

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 GABA 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.

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. 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.

32 Glutamate Primary excitatory neurotransmitter
Synthesized from glutamine or glucose Glutamate receptors (e.g., NMDA) subject to excitotoxicity The 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 system Not just elevated glutamate, but in relation to the lowered levels of inhibitory NT serotonin and GABA along with imbalances in the hormones MSG, aspartame – break down and increase levels of glutamate

33 Niciu, 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.

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. 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.

35 Neurotransmitter 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.

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 Both 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.

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 We 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

40 Dopamine = Experience of Reward
Low Dopamine = Low Pleasure = Anhedonia Remember Woody Allen & Annie Hall? Anhedonia – could call it lack of dopamine

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 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.

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 NE 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 increase GABA 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.

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):

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 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 overactivation Looks like exogenous cortisol does not help in this step, but endogenous does

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 CNS 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.

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 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


52 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 Dr. 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.

53 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

54 Changes in serum DHEA-S (DHEA Sulfate) level with age
(Redrawn from Finch and Mobbs, 1982)

55 DHEA: Biomarker for Aging?
May Help Prevent or Treat: Cardiovascular Disease Elevated Cholesterol Diabetes Cognitive Disorders/Alzheimer’s Allergic Disorders Osteoporosis Immune Dysregulation: CFIDS, HIV, SLE (Lupus) Cancer prevention In 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.

56 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.

57 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):

58 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): 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 doses Monitor levels Long-term effects are unknown Caution in those with history or family history of hormone related cancers Keep levels on the lower end of range. What for thyroid levels – will get sx in about 10%.

59 DHEA Quick Summary Impacts neurotransmitters: both excitatory and inhibitory Serves as neuroprotection to CNS hippocampal neurons Anti-stress role as antagonist to cortisol

60 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 I 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 cells These glands do not function on their own but await communication from the nerves that serve them Receptors for many neurotransmitters are located on the hypothalamus


62 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 Nature’s SSRI in women Koldzic-Zivanovic N, et al. Mol Cell Endocrinol Oct 29;26(1-2):33-42.

63 Estrogen’s 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 Estrogen’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):

64 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

65 Estrogen’s Effect on Neurotransmission
Women are twice as likely to suffer from mood disorders as men A 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

66 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.

67 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. Whether that be with hormones, herbals, or SSRIs, etc.

68 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 The 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.

69 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 (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.

70 Stress X

71 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

72 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 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.


74 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 I 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!”

75 Natural Testosterone Give in morning, preferably to correlate with diurnal secretion Common Dosage range: Women Men Oral: 1-10 mg/day Usually 2-5mg/day mg/day Usually 35-50mg/d Sublingual: 0.625mg–5 mg/day 10 mg – 35mg/day Transdermal: 0.5 – 8 mg/day 10mg – 50 mg/day

76 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):

77 Summary

78 Hormone Effects on NT’s
Estrogen: serotonin agonist, dopamine modulator Progesterone: GABA agonist Testosterone: serotonin agonist, dopamine agonist DHEA: dopamine, NE, serotonin agonist, GABA antagonist Neuro-protective, Neuronal plasticity Thyroid: serotonin agonist Cortisol excess: blocks serotonin and tryptophan metabolism into serotonin; use 5-HTP to bypass Cortisol deficiency:  serotonin, epinephrine  norepinephrine, glutamate Insulin excess (Insulin Res.): serotonin, NE, dopamine Hormones 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.

79 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 HPAT 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.

80 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. 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 reassess Patients 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.

81 We can positively affect how women and men transition through Life
It’s All About Balance

82 Do you feel like this??

83 In Summary… as well as living longer. True health is living well,
It is the art of balance and communication within the neuro-endocrine system.




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

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