Neuroendocrine Imbalance in
Patient Care
Leo Galland M.D.
Foundation for Integrated Medicine
CLINICAL VISION IS
WHAT THE DOCTOR
SEES
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Conventional Medical Vision
• People become sick because they
develop diseases.

The doctor looks for the disease that
occupies the patient.
 The name of this disease becomes the
diagnosis and the basis for treatment.
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Another Way of Seeing

People become sick because of disharmonies and
imbalances, which may involve:
Social relationships, environmental assaults,
problems of diet, lifestyle, behavior and belief
systems, and disturbances in the flow of energy
and information within the individual.
 The healer’s job is to identify and help the patient
correct these.
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Central Systems Mediate Functions
Needed for Coordinated Behavior of
the Whole Organism

•
Systems relating brain and body
-Autonomic nervous system
-Neuroendocrine system
-Neuroimmune system
Systems within the brain
-Specific and diffuse transmitter systems
-Distributed systems
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Central Systems Are Difficult
to Localize and Measure

Their output may be too widespread to
characterize adequately.
 Their actions may persist for days, months
or years.
 Although behaviors generated by central
systems can be observed and classified,
their neural substrates may be elusive.
Shepherd, Neurobiology 1994,
Chapter 24
Central Systems Interact with
One Another Continuously

Immune responses alter neuroendocrine
function.
 Endocrine responses alter neuroimmune
function.
 Neuroendocrine responses alter autonomic
nervous system function.
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Neuroendocrine Regulation
Maintains Homeostasis in
Response to Stressors

Prolonged stress causes allostasis, a new
equilibrium significantly different from the
resting state: levels of important
physiologic mediators are altered.
 Neuroendocrine imbalance is one
manifestation of allostasis.
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Neuroendocrine
Imbalance
 Is
a disruption in the flow of
information among cells and
between organs.
 Is not a specific disease but may
complicate many different
diseases.
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Glands and Hormones

Anterior pituitary


Posterior pituitary/
neurointermediate lobe

Pineal
 Thyroid
 Parathyroid




GH, PRL, ACTH,
TSH, FSH, LH
Arginine vasopressin,
oxytocin, endorphins,
enkephalins
Melatonin
T4, T3, calcitonin
PTH
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Glands and Hormones

Heart
 Adrenal cortex



Adrenal medulla
Kidney
 Skin
ANF
 Glucocorticoids,
mineralocorticoids,
androgens
 epinephrine,
norepinephrine

Renin, calcitriol
 Vitamin D
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Glands and Hormones

Liver/lung
 Pancreas
 GI tract




Gonads
Lymphocytes,
macrophages



Angiotensin
Insulin, glucagon
CK, VIP, bombesin,
somatostatin
Estrogen, progesterone
testosterone
Cytokines
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Hypothalamic Neuropeptides

CRF
 GnRF
 TRH
 GHRF, GHIF
 PRF, PIF
 Neuropeptide Y
 Leptin
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Classic Neurotransmitters

Catecholamines: DA, NE, EPI
 Indoles: 5 HT, Melatonin
 ACh
 Amino acids: GABA, Glutamate, Aspartate
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Biological Rhythms Reflect
Anticipatory Homeostasis

Dark increases melatonin which induces
sleep.
 Rest increases PRL which increases REM
sleep.
 CRH, vasopressin and neuropeptide Y
increase during sleep, preparing for
increased brain activation and foodsearching behaviors on awakening.
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Sleep Patterns Are Determined
by the Immune System

IL-1 induces Stage 4 sleep and stimulates
the HPA axis.
 In health, IL-1 production is cyclic.
 It is stimulated by muramyl peptides
derived from normal gut microflora.
 It is inhibited by glucocorticoids.
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REGULATORY PATHWAYS
• NE enhances hypothalamic CRH.
• Serotonin enhances ACTH secretion:
5HT deficits impair HPA output.
 NE neurons stimulate TSH:
Adrenergic deficits impair HPT
responses. Thyroid deficit impairs
adrenergic function.
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Vasopressin and the Brain

VP mimics/enhances CRH effects. Under stress,
some VP neurons produce CRH.
 Testosterone increases VP synthesis; some
testosterone-induced aggressive behaviors may be
VP mediated.
 NE increases CRH and VP production.
 Glucocorticoids decrease CRH/VP production in
the hypothalamus, not the amygdala.
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INFLAMMATORY MEDIATORS MAY
ALTER NEUROENDOCRINE
FUNCTION

CYTOKINES
 PROSTANOIDS
 ENZYMES
 MONOAMINES
 VARIOUS PEPTIDES
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EFFECTS OF
INFLAMMATION

Altered protein synthesis
 Neuroendocrine changes
 Hematopoietic changes
 Metabolic changes
 Altered micronutrient levels: zinc, iron ,
copper, magnesium, retinol, glutathione
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NEUROENDOCRINE
EFFECTS

Fever, somnolence, anorexia
 HPA axis stimulation
 Increased arginine vasopressin secretion
 Inhibition of IGF-1 synthesis
 Increased adrenal catecholamine secretion
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Autonomic Dysregulation

Neurally-mediated hypotension
 Sympathetic hyperreflexia
 Parasympathetic hypertonus
 Drug induced
 Denervation
 Classic dysautonomias
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Tests of the HPA Axis
• Serum cortisol at 800, 1600, 2400
• Cortisol response to ACTH
•
•
•
•
ACTH response to CRH
Serum DHEA-S
24 hour urine for cortisol, DHEA
Dexamethasone suppression
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Tests of the HPT Axis

T4, T3, TSH (third generation)
 TSH response to TRH
 Urinary excretion of T3, T4 ?
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References for
Neuroendocrine Testing

Dons RF: Endocrine and Metabolic testing
Manual, CRC Press, Third Edition 1998.
 Svirbely JR & Sriram MG, The Medical
Algorithms Project.
www.medal.org.ar/chapters/index.html
(Chapter 13)
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Clinical Indicators

Fatigue (conditional, fluctuating)
 Exercise intolerance
 Temperature intolerance (hot/cold)
 Abnormal temperature control
 Disordered patterns of sleep, appetite
 Difficulty losing/gaining weight
 Cardiac symptoms
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Physical Findings

Temperature, pulse, blood pressure
 Orthostatic change in pulse, blood pressure
 Pulse change with forceful handgrip
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Women with PMS Have
Impaired Serotonin Circuits

Women with PMS have an impaired
serotonin response to tryptophan and a
blunted cortisol response to serotonin.
 Impoved function of serotonin-dependent
pathways improves premenstrual
symptoms.
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Impaired Utilization of Tryptophan
in Women with PMS

Intravenous tryptophan produced a smaller
elevation of whole blood serotonin in
women with PMS than in controls.
 This effect occurred only during the luteal
phase.
 Does it explain the carbohydrate cravings
that are so common at this time?
Rasgon et al, Fertil Steril 2000
The HPT Axis Is Often
Abnormal in Depression

10% of hospitalized patients are
hypothyroid (TSH stimulation).
 For others, TSH response to TRH is
blunted, due to abnormal
neurotransmission.
 T3 is an effective anti-depressant, whatever
the neuroendocrine responses.
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The HPA Axis Shows Loss of
Negative Feedback in People
with Depression

Urine free cortisol is elevated, especially
when stressors cannot be controlled.
 Diurnal pattern may be disrupted, with
increased PM cortisol secretion.
 Dexamethasone suppression is blunted.
 Spinal fluid CRH is elevated (also in OCD
and post-traumatic stress disorder).
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The Amygdala and Allostasis

Receives information from all neocortical
sites and visceral input from brainstem.
 Involved in emotional memory.
 CRH production here is up-regulated by
glucocorticoids.
 Increased activation occurs in depression.
 CRH in the brain induces fear, withdrawal.
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EFAs and Depression

Impaired synaptic function due to a deficit
of omega-3 essential fatty acids (EFAs) may
contribute to the pathogenesis of CNS
disturbances in depression.
 (1) Maes M. Et al. Psychiatry Res (1998).
 (2) Peet M et al. Biol psychiatry (1998).
 (3) Adams PB. Lipids (1996).
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The HPA Axis in CFIDS

Cortisol response to exercise is blunted.
 ACTH response to CRH is blunted.
 As if patients are withdrawing from
exogenous steroids.
 DHEA response to ACTH is impaired.
 Low dose cortisone improves symptoms but
aggravates HPA suppression.
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T-Helper Cells in CFS Patients are
Ultrasensitive to Glucocorticoids

CD-4 lymphocytes from patients produce
less gamma-interferon than controls.
 Inhibition of cell proliferation and
production of gamma-interferon or IL-4 was
produced at 5-10% of the dose of
dexamethasone required for controls.
Visser et al, J Infect Dis 1998
Hypotension in CFIDS

Delayed orthostatic hypotension is
common.
 Fludrocortisone was ineffective in a
controlled study.
 Sodium loading relieves symptoms, perhaps
by stimulating vasopressin synthesis.
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Oral NaCl Improves CFS
Symptoms

One third of CFS patients had abnormal tilt
table tests.
 Sustained release NaCl, 1200 mg daily for 8
weeks improved tilt table responses and
symptoms in 50% of these.
 Non-responders had low plasma renin
activity.
DeLorenzo et al, Clin Auton Res
1997
Desmopressin improves HPA
Response to CRH in CFS

Patients with CFS have an impaired ACTH
and cortisol response to CRH.
 Desmopressin (a vasopressin analogue)
restores this to normal.
Scott et al, Biol Psychiatry 1999
Clinical Approaches

Symptom analysis:
- Fatigue (conditional, fluctuating)
- Exercise intolerance
-Temperature intolerance
• Physical findings:
-Unstable blood pressure
-Inappropriate temperature
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Dietary Influences

High protein, low carbohydrate diets may
decrease serotonin availability and deplete
volume.
 Omega-3 EFA deficit may impair serotonin
activity.
 Low sodium, high water intake depresses
vasopressin synthesis.
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Substances That May
Enhance HPA Activity

Sodium
 Phosphatidyl serine
 Siberian ginseng
 Maca
 Serotonin enhancers
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Substances That May Inhibit
HPA Activation

Water
 Benzodiazepines
 Exogenous steroids
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When Your Favorites
Treatments Don’t Work…

They may have undesirable neuroendocrine
effects.
 More time may be required because the
effects of central systems can be prolonged.
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