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Transcript
Adrenal Dysfunction:
The Role of Stress
Dr. Stephen Goldman
Genova Diagnostics
© 2012
2008
Adrenal Dysfunction:
The Role of Stress
Dr. Stephen Goldman
Genova Diagnostics
Sex
Hormones
Thyroid
Ad
Adrenals
l
© 2012
2008
Dr. Stephen Goldman
Teresa McBride, ND
© 2012
2008
Technical Issues
Clinical Questions
Clinical Questions will
be answered during the
final fifteen (15)
minutes of the webinar.
webinar
2010
© 2012
Clinical Concerns –
Hormonal Assessment
Sex
Hormones
Th id
Thyroid
Adrenals
2010
© 2012
Adrenal Dysfunction:
Si
Signs
& Symptoms
S
t
• Tired for no reason.
• Trouble getting up in the morning, even when you
go to bed at a reasonable hour
hour.
• Feeling rundown or overwhelmed.
• Difficulty bouncing back from stress or illness.
• F
Feell more awake,
k alert
l t and
d energetic
ti after
ft 6PM
than you do all day.
2010
© 2012
Adrenal Dysfunction:
P th h i l
Pathophysiology
• The adrenal glands produce the hormones
cortisol and DHEA.
• Over secretion of cortisol triggered by daily
stress from work, family or other sources
can wear down the internal system and
cause fatigue.
• During this process DHEA may be
compromised,
i d causing
i other
th ffunctions
ti
tto
suffer.
2010
© 2012
Corttisol Le
evels
HPA Resiliency and Aging
Aged
espo se
Response
(Less Resilient)
Stress Event
Young
Response
(“Resilient”)
Time
(Seeman TE 1994)
2010
© 2012
What Constitutes “Stress?
• “Fight
Fight or flight
flight” responses; fear
fear,
anxiety, worry
• Depression,
Depression feelings of defeat or
helplessness
• Pain syndromes
• Infection, inflammation
• Hypoglycemia
H
l
i
• Inadequate sleep
• Disrupted light cycles
p
• Toxic exposure
2010
© 2012
2010
© 2012
STRESS
HPA Axis
Hypothalamus
& Pituitary
ACTH
Adrenal Cortex
DHEA
(anabolic)
Cortisol
C
ti l
(catabolic)
Stress
2010
© 2012
Cholesterol
Pregnenolone
Progesterone
THE STEROIDOGENIC PATHWAYS
17-OH-Pregnenolone
17-OH-Progesterone
17
OH Progesterone
DHEA
Androstenediol
Androstenedione
Testosterone
DHT
Corticosterone
Cortisol
(Glucocorticoids)
(A d
(Androgens)
)
Estrone ((E1))
Estradiol ((E2))
Aldosterone
2-OHE1
(Mineralocorticoids)
16α-OHE1
4 OHE1
4-OHE1
2-MeOE1
Estriol (E3)
4 MeOE1
4-MeOE1
(Estrogens)
Cholesterol
Pregnenolone
Progesterone
17-OH-Pregnenolone
17-OH-Progesterone
17
OH Progesterone
DHEA
Androstenediol
Androstenedione
Testosterone
DHT
Corticosterone
Cortisol
(Glucocorticoids)
(A d
(Androgens)
)
Estrone ((E1))
Estradiol ((E2))
Aldosterone
2-OHE1
Cortisol & DHEA
derive from
same precursors
16α-OHE1
4 OHE1
4-OHE1
2-MeOE1
Estriol (E3)
4 MeOE1
4-MeOE1
(Estrogens)
Saliva
Plasma
Blood
(bound + free)
Basement
membrane
Saliva
Saliva
(only free)
Basement
membrane
2010
© 2012
2010
© 2012
Stage - One
2010
© 2012
2010
© 2012
Stage - Two
2010
© 2012
Stage - Three
2010
© 2012
Cholesterol
The Steroidogenic Pathways
(Anabolic)
Pregnenolone
Androstenediol
DHEA
17-OH-Pregnenolone
Progesterone
Androstenedione
Testosterone
DHT
Aldosterone
Cortisol
Cortisone
(Catabolic)
Androsterone
Estrone
(E1)
Androstanediol
Estradiol
(E2)
Cholesterol
The Steroidogenic Pathways
(Anabolic)
Pregnenolone
Androstenediol
DHEA
17-OH-Pregnenolone
Progesterone
Androstenedione
Testosterone
DHT
Aldosterone
Cortisol
Cortisone
(Catabolic)
Androsterone
Estrone
(E1)
Androstanediol
Estradiol
(E2)
Cholesterol
Pregnenolone
(Anabolic)
Progesterone
Androstenediol
DHEA
17-OH-Pregnenolone
Androstenedione
Testosterone
DHT
Aldosterone
Cortisol
Cortisone
(Catabolic)
Androsterone
Estrone
(E1)
Androstanediol
Estradiol
(E2)
“Cortisol Steal”
• St
Stress off acute
t immobilization
i
bili ti iin rats
t  inhibition
i hibiti
of 17α-hydroxylase and 17,20 lyase (Orr Te 1994)
• Severe illness  relative shift in pregnenolone
away from androgens and mineralocorticoids, and
toward glucocorticoids  increased serum and
urine cortisol (Parker LN 1985)
• Serum cortisol:DHEA-S ratio higher in elderly hip
patients compared
p
with controls;; reduced
fracture p
immunity in these patients (Butcher SK 2005)
2010
© 2012
Patient Case Hx
49 year old male, executive presents with:
• increasing fatigue
• poor sleep & difficulty arising
• decreased libido and strength
• mild
ild d
depression
i
Initial work-up negative for thyroid problems.
p Metabolic Profile
Normal CBC & Comp
2010
© 2012
Tests
• Diagnostic
g
– Adrenocortex Stress Profile
– Complete Hormones (urine)
• Health Related Issues
– Comprehensive Thyroid Assessment
– Sex Hormones – result in deficiencies
(precursor hormones)
2010
© 2012
Salivary Cortisol and DHEA
2010
© 2012
Cholesterol
Pregnenolone
Progesterone
17-OH-Pregnenolone
17-OH-Progesterone
17
OH Progesterone
DHEA
Androstenediol
Androstenedione
Testosterone
DHT
Corticosterone
Cortisol
(Glucocorticoids)
(A d
(Androgens)
)
Estrone ((E1))
Estradiol ((E2))
Aldosterone
2-OHE1
Cortisol & DHEA
derive from
same precursors
16α-OHE1
4 OHE1
4-OHE1
2-MeOE1
Estriol (E3)
4 MeOE1
4-MeOE1
(Estrogens)
Cholesterol
Pregnenolone
17-OH-Pregnenolone
Progesterone
Androstenediol
DHEA
Androstenedione
Testosterone
DHT
Aldosterone
Cortisol
Cortisone
“CORTISOL
CORTISOL STEAL
STEAL”
Androsterone
Estrone
(E1)
Androstanediol
Estradiol
(E2)
Stress and Steroid Synthesis
“Wear and Tear”
vs. “Rest and Recovery”
2010
© 2012
STRESS
N
Normal Stress Response
l St
R
(+)
Hypothalamus
& Pit
Pituitary
it
Sympathetic
response
(alarm)
(cortisol
p
)
receptors)
(-)
(ACTH)
(negative
feedback
loop)
Adrenal Cortex
DHEA
CORTISOL
(Anabolic)
(C t b li )
(Catabolic)
2010
© 2012
A i
Actions
off Cortisol
C i l – Catabolic
C b li
• Maintains blood glucose levels during stress
(gluconeogenesis)
g
)  additional
reactions (g
glucose to brain, heart, lungs, skeletal muscle
• Promotes hepatic protein synthesis and
gluconeogenesis; stimulates protein catabolism
elsewhere in body
• Stimulates glycogenolysis, lipolysis
• Participates with aldosterone in Na reabsorption
 maintenance of perfusion pressures to critical
organs during stress
2010
© 2012
A i
Actions
off Cortisol
C i l – Catabolic
C b li
• Anti-inflammatory – downregulates
phospholipase
p
p
p
A2,, inflammatory
y cytokines
y
• Inhibitory feedback to hypothalamus and
pituitary  downregulation of CRH and ACTH
• Cortisol highest in a.m., with gradual decline
over course off day;
d
normall di
diurnall curve
indicates healthy adaptation to stress
2010
© 2012
Cortisol: Normal Diurnal Curve
2010
© 2012
Actions of DHEA – Anabolic
•
•
•
•
•
•
Prohormone
P
h
ffor sex steroids
t id
Anti-glucocorticoid
Immune supporting
Anti-atherogenic
Anti
atherogenic, lowers serum triglycerides
Enhances insulin sensitivity; anti-obesity effect
M i t i tissue
Maintains
ti
strength
t
th and
d repair,
i supports
t
bone density
• Neuroprotective; enhances memory
• Promotes sense of well-being
g
2010
© 2012
DHEA
• Long-term indicator of DHEA status
• Maximal values at 20 and 30 years of age;
thereafter, both DHEA and DHEA-S decrease
markedly…
2010
© 2012
DHEA & DHEA S (serum): Effects of Aging
DHEA & DHEA‐S (serum): Effects of Aging
Serum
DHEA
(nmol/L)
DHEA-fatty
acid esters
(nM)
Serum DHEA-S
(nmol/L)
Serum
androstenediol
(nM)
(Labrie F 2005)
2010
© 2012
DHEA
(March, 2007 study of African-American women
(March
women,
aged 49-65 years)…
“DHEA-S and E2 declined between the ages of 49
and 65 years, whereas total testosterone, SHBG
and the Free Androgen Index remained
stable…Lower DHEA-S levels were
independently associated with a higher degree of
physical disability and depressive symptoms.”
(Haren MT 2007)
2010
© 2012
Clinical Concerns –
Hormonal Assessment
Sex
Hormones
Comprehensive Thyroid
A
Assessment
t
How to Review a Report
Th id
Thyroid
Adrenocortex Stress
Profile
How to Review a Report
Adrenals
Steroid Balance
How to Review a Report
2010
© 2012
HPA Axis
STRESS
HPT Axis
Hypothalamus
& Pituitary
Hypothalamus
& Pituitary
ACTH
TSH
Adrenal Cortex
Thyroid
T4
DHEA
(anabolic)
Cortisol
C
ti l
(catabolic)
Liver
& Kidney
rT3
T3
Cell
Nucleus
2010
© 2012
Adrenocorticol Hyperactivity
• Life-saving in the short-term! (catabolism frees
up energy reserves)
• Persistent cortisol production  immune
suppression,
pp
, hyperglycemia,
yp g y
, insulin resistance,,
central adiposity, hypertension, memory
p
((hippocampal
pp
p damage),
g ),
impairment
hyperlipidemia, impaired hepatic T4T3
conversion
2010
© 2012
Hypothalamus
TRH
Pituitary
TSH
H
Liver or
Li
Kidney
(5’deiodinase)
(Se)
rT3
T3
T3
(Inactive) (Active) ~ 85%
Thyroid Gland
5% T3
(5 deiodinase)
95% T4
Cell
Nucleus
2010
© 2012
TRH
Hypothalamus
Pituitary
TSH
H
Liver or
Li
Kidney
95% T4
rT3
T3
T3
(Inactive) (Active)
5% T3
STRESS
Thyroid Gland
Cell
Nucleus
2010
© 2012
Adrenocorticol Hypoactivity
• High CRH is also possible in adrenal
hypoactivity (lack of inhibitory cortisol feedback
p
persistent output
p of CRH  excessive
adrenalin production)
g , hypotension,
yp
,
• Low cortisol fatigue,
hypoglycemia, sugar cravings, increased
inflammatory response,    conversion T4 to T3.
2010
© 2012
TRH
Hypothalamus
Pituitary
TSH
H
Liver or
Li
Kidney
95% T4
rT3
T3
T3
(Inactive) (Active)
5% T3
Chronic
Stress
Thyroid Gland
Cell
Nucleus
2010
© 2012
Factors Promoting
Conversion of T4 to T3
Micro-nutrients:
selenium, potassium, iodine, iron, zinc
Vitamins:
A E
A,
E, riboflavin
Hormones:
cortisol (physiologic doses)
growth hormone, testosterone
i
insulin,
li glucagon
l
melatonin
2010
© 2012
Case Study
55yo Female
• Menopausal x 3 years
• G3P1 (SAB2)
y
• Menarche @ 13yo
• + Fam Hx Breast CA and Prostate CA
• Patient with excellent diet of vegetables and fruits
Symptoms:
• Problems with climacteric symptoms, decreased libido, sleep
problems
• Began on TD Cream – BiEst (1mg), Progesterone (20mg),
Testosterone (0.5mg) – 6 months prior
• Symptoms persist, particularly evening anxiety and sleep
disturbance.
2010
© 2012
Case Studyy
Cortisol = Low normal DHEA = Low ((age-adjusted)
g
j
)
2010
© 2012
Case Study
Imbalance = Sex Hormones
• Measure Sex Hormones with Complete
Hormones (Urine)
– Balance Progesterone, Estrogens, & Testosterone
Imbalance = Adrenal Hormones
• Support Adrenals
–
–
–
–
Supplement with DHEA 10mg qD
B-Vitamins ((B2, B6, B12, Folate)) + Vitamin C
Adrenal Herbs (Ashwaghanda, Rhodiola)
Heart Rate Variabilityy BioFeedback
2010
© 2012
Case Studyy
2010
© 2012
Cholesterol
Pregnenolone
(Anabolic)
Progesterone
Androstenediol
DHEA
17-OH-Pregnenolone
Androstenedione
Testosterone
DHT
Aldosterone
Cortisol
Cortisone
(Catabolic)
Androsterone
Estrone
(E1)
Androstanediol
Estradiol
(E2)
STRESS
N
Normal Stress Response
l St
R
(+)
Hypothalamus
& Pituitary
Sympathetic
response
(alarm)
(cortisol
p
)
receptors)
(-)
(ACTH)
(negative
feedback
loop)
Adrenal Cortex
DHEA
CORTISOL
2010
© 2012
Personalizing Hormone P
li i H
Diagnosis & Treatment:
The Whole Picture
Patrick Hanaway,
Hanaway MD
© 2012
2008
Questions & Answers
Register for upcoming LiveGDX Webinars
g
online @ www.gdx.net
2010
© 2012
2010
© 2012
2010
© 2012
2010
© 2012
LiveGDX
2010
© 2012
Upcoming LiveGDX Webinars
The Endocrine Pyramid
• 5/23/12 –Thyroid Dysfunction:
» Nutrients & Toxins
• 6/27/12 – Sex Hormone Dysfunction:
y
» The Role of Stress, Nutrients & Inflammation
Sex
Hormones
Thyroid
Adrenals
2010
© 2012