Understanding the HPA-T Axis with Relation to

Hormone Imbalance

R.W. Watkins, MD, MPH, FAAFP Sanesco Roundtable

4 May 2013Charlotte, 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

Introductions

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 person’s neurotransmitter balance

How can I use this information?

Initial Assessment of patientWhat 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 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 PathwaysAmino Acids precursors to NeurotransmittersAmino Acid Therapy

Pharmaceutical research suggested drug-based mechanisms for neuromodulationSSRI’s (Prozac 1987)SNRI’s. (Wellbutrin 1989, etc.)

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

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. 2006 Mar;109(3):325-38. 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. 1979 Oct;105(4):975-9.

Giving 5-HTP can make TSH rise while serotonin depletion makes TSH fall.

Chen HJ, Meites J. Endocrinology, 1975;Vol 96, 10-14.

Increases in serotonin are paralleled by increases in TSH.

Karamouzis M, et al. Hell J Nucl Med. 1999;2:125-30.

Serotonin and Thyroid

Giving T3 induces a rise in serotonin

In animals with hypothyroidism, serotonin synthesis is reduced

Sintzel F, et al. Encephale. 2004 May-Jun;30(3):267-75.

Proposed mechanism of action: T3 desensitizes presynaptic serotonin autoreceptors

Bauer M, et al. Mol Psychiatry. 2002;7(2):140-56.

Serotonin and Thyroid

Optimal thyroid function, beyond simply being within the normal laboratory values, may be necessary for an optimal response to antidepressants.

Gitlin M, et al. J Psychiatry Neurosci 2004;29(5):383-6.

The thyroid hormone, triiodothyronine (T3), augments and accelerates the effects of antidepressant drugs.

Fluoxetine + T3 better at desensitizing 5-HT hypothalamic autoreceptors than either alone.

Lifschytz T, et al. J Neurosci Methods. 2004 Dec 30;140(1-2):133-9.

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. 2004 Jan;28(1):119-25.

2. Corticosterone treatment significantly decreased the number of 5-HT1A receptor sites . . . Crayton JW, et al. Brain Res. 1996 Jul 29;728(2):260-2.

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):96-104.

4. “Transcription of the gene coding for tryptophan oxygenase (TO) in rat liver is induced 10-fold by glucocorticoids”

NOTE: 5-HTP bypasses the TO enzyme and thus can raise serotonin even in the face of excess cortisol

Danesch U, et al. EMBO J. 1987 Mar;6(3):625-30.

Low Cortisol and Serotonin

“[In the amygdala], if endogenous cortisol is removed, 5-HT no longer has an inhibitory effect on glutamatergic activity, suggesting that this hormone (Cortisol) plays a key role in maintaining serotonergic-mediated modulation”.

Stutzmann GE, McEwen BS, LeDoux JE. J Neurosci. 1998

Nov.15;18(22):9529-38.

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

Panic attack

GABA Too much excitation without adequate GABA

inhibition can lead to: Insomnia

Restlessness Irritability

AnxietyPanic AttacksSeizures

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):656-664. 2012.

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.

Neurotransmitter Pathways“The CATS”

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

CATs in balance

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 postureCognitive function: attention, focus,

working memory and problem solvingMotivation for reward

Neuromodulator: can act either as an Inhibitory or Excitatory NT in response to incoming afferent signals

Dopamine = Experience of Reward

Low Dopamine = Low Pleasure =

Anhedonia

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. 2004 Mar 31;24(13):3235-41.

SSRI’s shown to increase the dopamine transporter in vivo, thereby reducing dopamine function.

Kugaya A, et al. Neuropsychopharmacology. 2003 Feb;28(2):413-20.

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

Norepinephrine

Over-expression of CNS norepinephrine clinically associated with:Anxiety, Aggression, Irritability, Mania or

Bipolar Disease, Immune Suppression, Hypertension and CHF

Low Norepinephrine associated with “Atypical Depression” with symptoms of:Fatigue, Hypersomnia, Hyperphagia,

Lethargy and Apathy

Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry. 2002;7(3):254-75.

Atypical Depression

Validity as a Clinical Tool

Recently released publication on theValidity of Urinary Neurotransmitter Testingwith Clinical Applications ofthe CSM™ (CommunicationSystem Management) Model

22-page document with 117 references from the medicalliterature

Adrenal Fatigue & NT Balance

“Adrenal Fatigue”, with cortisol and DHEA depletion, can lead to a low epinephrine level and elevated Norepi/Epi ratio

Adequate cortisol is needed for the precursor NE to be converted to epinephrine

SAMe

Norepinephrine cortisol Epinephrine

Zuckerman-Levin, et al. The importance of adrenocortical glucocorticoids for adrenomedullary and physiological response to stress: a study in isolated glucocorticoid deficiency. J Clin Endocrinol Metab. 2001 Dec;86(12):5920-4.

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. 2002 Nov 19;106(21):2659-65.

Epinephrine

3 phases of stress responsePhase I: Alarm reaction: Hi Epi/Hi CortisolPhase II: Resistance: Hi Cortisol/Low DHEA

Epi variablePhase 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 20 - 30)

↓↓ DHEA/S & Cortisol

DHEA Levels and Age

200

600

1000

1400

1800

2200

2600

3000

3400

3800

10 20 30 40 50 60 70

years

ng

/ml

pla

sma

Women

Men

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/Alzheimer’s Allergic Disorders Osteoporosis Immune Dysregulation:

CFIDS, HIV, SLE (Lupus)

Cancer prevention

DHEA & Neurotransmitters

Inhibits GABA; is a GABA antagonist Shen W, et al. Neuropharmacology. 1999 Feb;38(2):267-71.

Increases dopamine & norepinephrine synthesis via mRNA for tyrosine hydroxylaseCharalampopoulos I, et al. Endocrinology. 2005 Aug;146(8):3309-18.

Increases firing activity of serotonin neurons Robichaud M, Debonnel G. J Endocrinol. 2004 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. 1998 Feb 17;95(4):1852-7.

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. 1990 Sep;71(3):696-704.

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. 1994 Sep;37(9):1305-10.

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

FatigueInsomniaMigrainesHot flashes/vasomotor instabilityDecreased brain function/memory issuesDepression/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. 1990 Jun 4;518(1-2):287-91.

Estrogen increased the firing activity of 5-HT neurons in both male and female rats.

Robichaud M, Debonnel G. J Neuroendocrinol. 2005 Mar;17(3):179-85.

Estrogen inhibits serotonin reuptake. It is Nature’s SSRI in women

Koldzic-Zivanovic N, et al. Mol Cell Endocrinol. 2004 Oct 29;26(1-2):33-42.

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):189-203.

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

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.

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. 2008 Feb;121(2):159-162.e1.

Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003 Jun 4;289(21):2827-34.

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. 2008 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. 2008 Jun 20;60(2):148-52.

Koldzic-Zivanovic N, Seitz PK, Watson CS, Cunningham KA, Thomas ML. Intracellular signaling involved in estrogen regulation of serotonin reuptake. Mol Cell Endocrinol. 2004 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):CD001396.

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

Stress

X X X

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 GABAA receptors.

Marx CE. Psychiatric Times. 2001 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. 2002 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:

Women Men

Oral: 1-10 mg/dayUsually 2-5mg/day

25 -75 mg/dayUsually 35-50mg/d

Sublingual: 0.625mg–5 mg/day 10 mg – 35mg/day

Transdermal: 0.5 – 8 mg/day 10mg – 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. 1988 Mar-Apr;14(2):177-87.

“Testosterone increases serotonergic neuron firing in the raphe area, increasing mood”.

Robichaud M, Debonnel G. J Neuroendocrinol. 2005 Mar;17(3):179-85.

“Testosterone increases central nitric oxide synthase; nitric oxide increases dopamine release, necessary for sexual motivation”.

Hull EM, et al. Physiol Behav. 2004 Nov 15;83(2):291-307.

Summary

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

NT Effects on Hormones

Serotonin: thyroid functionNecessary 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

It’s 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 theneuro-endocrine system.

Understanding the HPA-T Axis with Relation to

Hormone Imbalance

R.W. Watkins, MD, MPH, FAAFP Sanesco Roundtable

4 May 2013Charlotte, NC