Transcript INTEGRATE – Charlotte, NC – Dr. Watkins, MD

Understanding the HPA-T Axis
with Relation to
Hormone Imbalance
R.W. Watkins, MD, MPH, FAAFP
Sanesco Roundtable
4 May 2013
Charlotte, NC
Introductions
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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
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Develop an overview of the
interconnectedness of the neuroendocrine
communication system
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Identify the major neurotransmitters and
their function
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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 proinflammatory degenerative diseases
 Imbalance in the Communication System can
contribute to hormonal imbalances
Neurotransmitters:
The tip of the iceberg
Natural Hormones: Evaluation for
NT-HRT
H & P and laboratory
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CBC
 2:16 Estrogen Metabolite Ratio
SMAC 20 with lipids
 Iodine levels (24 hr. urine)
TSH, fT3 , fT4, rT3
 Mammography
Thyroid auto-antibodies
 Pap Smear
Estradiol (E2), Progesterone
 DEXA scan of hip and spine
Free & Total Testosterone
 PSA (males)
DHEA-S
 Prolactin (if indicated)
Pregnenolone
 Sonography (if indicated)
FSH, LH
 Intracellular minerals
SHBG (Sex Hormone Binding  3-Hour GITT: Insulin
Globulin)
Resistance Test
 TBG (Thyroid Binding
 Neurotransmitter levels
Globulin)
(spot urine sample)
 DHT (Dihydrotestosterone)
 AI: Adrenal Index (saliva)
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 patient
 What is the current state of their nervous and
hormonal systems?
 Helps you guide therapy
 Is patient on SSRI or SNRI?
 Other medications that can effect NTs?
 Helps you monitor patient progress
 Helps you maintain patient improvements
Early Research on NTs
 Research began in the 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.)
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 = 5hydroxytryptophan, AADC = aromatic L-amino acid decarboxylase,
SNA = serotonin N-acetylase, HOMT = hydroxyindole-Omethyltransferase
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 5hydroxytryptophan. 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(12):133-9.
Serotonin and Thyroid
Thyroid function and Serotonin function are
Interdependent both clinically and biochemically
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 5HT(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
 Anxiety
 Panic Attacks
 Seizures
 GABA induces relaxation, calmness, aid sleep
 Theanine, Lactium (milk peptides), taurine, inositol,
and oral bio-identical progesterone can act as
nutraceutical GABA agonists
 Barbiturates, benzodiazepines and alcohol (dose
related) act as GABA agonists
Alterations in the gamma-aminobutyric acid
(GABA) receptor complex and GABA
neurotransmission influence the reinforcing and
intoxicating effects of alcohol and
benzodiazepines. Withdrawal symptoms stem
in part from a decreased GABAergic inhibitory
function and an increase in glutamatergic
excitatory function.
Malcolm RJ.GABA systems, benzodiazepines, and substance dependence.
J Clin Psychiatry. 2003;64 Suppl 3:36-40.
Glutamate
 Primary excitatory neurotransmitter
 Synthesized from glutamine or glucose
 Glutamate receptors (e.g., NMDA)
subject to excitotoxicity
Niciu, MJ. Kelmendi, B., et
al. Overview of
Glutamatergic
Neurotransmission in the
Nervous System.
Pharmacol Biochem Behav.
100(4):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-4hydroxyphenylglycol, 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 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
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 overexpressed resulting in delusional thinking, hypomanic/ 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 the
Validity of Urinary Neurotransmitter
Testing
with Clinical Applications of
the CSM™ (Communication
System Management) Model
22-page document with
117 references from the medical
literature
Adrenal Fatigue & NT Balance
 “Adrenal Fatigue”, with cortisol and DHEA
depletion, can lead to a low epinephrine level
and elevated Norepi/Epi ratio
 Adequate cortisol is needed for the precursor
NE to be converted to epinephrine
Norepinephrine
SAMe
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 response
 Phase I: Alarm reaction: Hi Epi/Hi Cortisol
 Phase II: Resistance:
Hi Cortisol/Low DHEA
Epi variable
 Phase III: Exhaustion: Depletion of Cortisol, Epi, DHEA
Most patients presenting to
my office are in the
resistance/exhaustion phase
of adrenal adaptation
DHEA: A Central Neuroactive Steroid
The most abundant adrenal hormone produced in the
zona reticularis of the adrenal cortex
DHEA/S is synthesized from pregnenolone under the
influence of pituitary ACTH
Precursor to both estrogen & testosterone especially
important after menopause and andropause
Anti-Stress role physiologically to balance & modulate the
effects of excess cortisol
Adrenopause: Age related decline in function of the
adrenal cortex characterized by: (age onset 20 - 30)
↓↓ DHEA/S & Cortisol
DHEA Levels and Age
3800
3400
ng/ml plasma
3000
2600
2200
Women
Men
1800
1400
Changes in serum DHEA-S
(DHEA Sulfate) level with age
1000
600
200
10
20
30
40
50
60
70
years
(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
hydroxylase
Charalampopoulos 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.
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DHEA appears to be safe at physiologic doses
Monitor levels
Long-term effects are unknown
Caution in those with history or family history of hormone
related cancers
DHEA Quick Summary
 Impacts neurotransmitters: both excitatory
and inhibitory
 Serves as neuroprotection to CNS
hippocampal neurons
 Anti-stress role as antagonist to cortisol
Transitional Years
 35 years – anovulation -
progesterone
Anxiety, loosing sleep - GABA
 45 years - estrogen - serotonin
Fatigue
Insomnia
Migraines
Hot flashes/vasomotor instability
Decreased brain function/memory issues
Depression/Anxiety/Emotional volatility
Estrogen supports Serotonin…
 Estrogen treatment shown to selectively enhance
5-HT1A-mediated responses in the hippocampus.
Clarke WP, Maayani S. Brain Res. 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.
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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
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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
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 5reductase 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
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Vaginal dryness
Thinning Skin
Bone Loss
Aches/pains
Urinary Incontinence
Decreased Muscle
Mass
 Increased Fat depot
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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/day
25 -75 mg/day
Usually 2-5mg/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
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
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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 function
Necessary to  TSH appropriately for feedback loop
stimulation of fT3 and fT4
Adrenal support; cortisol appropriately
GABA: Inhibits thyroid function
Dopamine: Prolactin, Growth Hormone
NE excess: Acute: Cortisol
Chronic: Cortisol
Epinephrine excess: Insulin Resistance - Insulin
Neuro-Endocrine Balance
 An imbalance in any one aspect of NT or
hormone system leads to a compensatory
imbalance of both systems
 Imbalance perpetuates imbalance
 Re-establishment of optimal balance IS
possible
 Assessment is accomplished through serum
and saliva hormone levels and urinary levels
of NTs, along with clinical improvements.
We can positively affect how women and
men transition through Life
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 the
neuro-endocrine system.
Understanding the HPA-T Axis
with Relation to
Hormone Imbalance
R.W. Watkins, MD, MPH, FAAFP
Sanesco Roundtable
4 May 2013
Charlotte, NC