D-Adrenal Physiology and
Hypofunctioning States
Goals of Discussion
Review
Adrenal Physiology
Identify the clinical features of Adrenal
Insufficiency
Etiologies of Adrenal Insufficiency
Understand testing of adrenal function
Treatment of Adrenal Insufficiency
Adrenal Development
Derived
– Neuroectodermal cells
(medulla)
– Mesenchymal cells (cortex)
Fetal adrenal is present by 2
months gestation
– Mostly cortex
– Glomerulosa and fasiculata are
present at birth
– Reticularis develops during first
year of life
Adrenal Anatomy
Adult adrenal
– 2-3cm wide
– 1cm thick
– 4-6 grams
Located
– Upper pole of kidneys
Vascular supply
– 12 small arteries from
aorta
Adrenal Physiology
Glomerulosa
– 15% of cortex
– Aldosterone
Renin-Angiotensin
Fasciulata
– 75% of cortex
– Cortisol
– DHEA
ACTH
Reticularis
– Androgens and estrogens
ACTH
Medulla
– Catecholamines
Congenital Adrenal Hyperplasia
Deficiency of CYP 17
– 17α- hydroxylase and 17-20
lyase deficiency
– Rare cause
– Diagnosed due to delayed
pubertal development
– 46xx
Hypertensive
+/- Hypokalemic
Primary amenorrhea
Absent secondary sex
characteristics
Congenital Adrenal Hyperplasia
Most adrenal
biosynthetic defects
result in
– Virilized female
– Normally virilized male
– Deficiencies
Mineralocorticoid
Glucocorticoid
– 21-OH deficiency
– 11-OH deficiency
Congenital Adrenal Hyperplasia
Deficiency of CYP 17
– 46XY
Complete male
pseudohermaphroditism
Female external genitalia
Blind-ended vagina
No mullerian structures
Testes intra-abdominal
– Leydig cell hyperplasia
Hypertensive
+/- Hypokalemic
Cortisol sufficient
– Tolerates general
anesthesia and surgery
Treatment
– Steroids to suppress
excess
– Gonadal replacement
Congenital Adrenal Hyperplasia
3 β-Hydroxysteroid
Dehydrogenase
– Presents early infancy
– Adrenal insufficiency
– Females can be virilized
due to DHEA
– Males
Normal genital development
Hypospadias
Pseudohermaphroditism
Can present in puberty
– Hyperandrogenemia
Hirsuitism
Oligomenorrhea
Treatment
– Cortisol replacement
Congenital Adrenal Hyperplasia
Congenital Lipoid Adrenal
Hyperplasia
StAR Deficiency
– Transports cholesterol to inner
mitochondrial membrane
Rarest form
Autosomal recessive
All adrenal steroids are
deficient
Present with adrenal
insufficiency
Typically fatal infancy
Males
– Female external genitalia
Renin and Aldosterone
Renin
– Enzyme released from the kidneys
(macula densa)
– Activates Angiotensinogen
Angiotensin 1
Angiotensin 2
– Increased secretion
Low blood pressure
Low sodium
High potassium
Upright posture
Aldosterone
– Sodium homeostasis
– Regulates arterial pressure
– Regulated
Angiotensin 2
– Increases
Renal sodium retention
Renal potassium excretion
– Low Aldosterone
Adrenal insufficiency
– High renin
Hyperkalemia
Renin and Aldosterone
Mineralocorticoid Deficiency
Hyporeninemic
Hypoaldosteronism
– Impaired renin release
– 50-70 years
– Chronic assymptomatic
hyperkalemia
– Mild-moderate renal
insufficiency
– Muscle weakness
– Cardiac arrhythmias
Mineralocorticoid Deficiency
50% of patients with
Diabetes
Type IV RTA
– Metabolic acidosis
– Decreased renal
ammoniagenesis
– Decreased H ion secretion
– Decreased bicarbonate
resorbtion
Other diseases
–
–
–
–
–
–
–
SLE
Multiple myeloma
Renal amyloidosis
Cirrhosis
Sickle Cell
AIDS
POEMS
Transient with drugs
–
–
–
–
NSAID
Cyclosporin A
Mitomycin C
Cosyntropin
Mineralocorticoid Deficiency
Primary Hypoaldosteronism
Aldosterone synthase
deficiency (CYP11B2)
– Autosomal recessive
– Diagnosed in infancy
Recurrent dehydration
Failure to thrive
Salt wasting
Treatment
– Florinef
Acquired
– Heparin
Suppresses aldosterone
Increase in renin
Healthy person,
asymptomatic
Critically ill, can be
symptomatic
Mineralocorticoid Deficiency
Primary Hypoaldosteronism
Pseudohypoaldosteronism
– Salt wasting syndrome
– Infancy
– Renal tubular insensitivity to
mineralocorticoids
– Autosomal Dominant
Resistance to aldosterone at the
renal tubule
–
–
–
–
Hyopnatremia
Hyperkalemia
Hyper-reninemia
Increased aldosterone levels
Many kindreds
– Homozygous mutation in
amiloride-sensitive epithelial
sodium channel
– Autosomal Recessive
Severe
Also affects sweat and salivary
glands
Colon
Features of
hypoaldosteronism
Treatment
– NaCl
– K+ binding resins
HYPOTHALAMUS
(-)
HYPOTHALAMICPITUITARY
PORTAL SYSTEM
(-)
CRH
(+)
ANTERIOR
PITUITARY
POSTERIOR
PITUITARY
ACTH
Adrenal Fasiculata
CORTISOL
Adrenal Physiology
ACTH and cortisol
–
–
–
–
Pulsatile secretion
Highest in AM at wakening
Lowest late afternoon and evening
Nadir is 1-2 hrs after the start of
sleep
– Circadian
– Hypoglycemia
– Surgery
– Illness
– Hypotension
– Smoking
– Cold exposure
Blind patient
Reverts to a 24.5-25hr
– DHEA and Androstenedione
regulated by ACTH
Increase in response to
stress
Blunted response
– Chronic illness
Circulation of Cortisol and Adrenal Androgens
Secreted unbound
In circulation bind to
plasma proteins
Unbound is active
Cortisol
– Free (10%)
– Corticosteroid-binding
globulin (CBG) (75%)
– Albumin
Androgens
– Albumin
– Testosterone
Sex Hormone binding
(SHBG)
Cortisol Effects
Connective Tissue
– Inhibit fibroblasts
– Loss of collagen
– Thinning of skin
Bone
– Inhibit bone formation
– Stimulate bone resorption
– Potentiate actions of PTH
Increased resorption
Calcium metabolism
– Decrease intestinal
calcium absorption
– Stimulates renal 1αhydroxylase
Increases 1,25 OH vitamin
D synthesis
– Increased calciuria
– Increased phosphaturia
Cortisol Effects
Growth
– Accelerate development of
fetal tissues
– Inhibit linear growth
Erythrocytes
– Decreases IL-1
Decreased growth hormone
Immunologic
– Inhibit prostaglandin
synthesis
Lung maturity
– Minimal effect
Leukocytes
– Increase PMN by increasing
release from bone marrow
– Decreases lymphocytes,
monocytes and eosinophils
Phospholipase A2
IL-1 stimulates CRH and
ACTH
– Impairs AB production
and clearance
Cortisol Effects
Cardiovascular
– Increase CO
– Increase peripheral vascular tone
– Hypertension
Renal function
– Mineralocorticoid receptors
Na retention
Hypokalemia
HTN
– Glucocorticoid receptors
Increased GFR
Nervous system
– Enters the brain
– Euphoria
– Irritability, depression and
emotional lability
– Hyperkinetic or manic
behavior
– Overt psychosis
– Increased appetite
– Impaired memory or
concentration
– Decreased libido
– Insomnia
Decreased REM and increased
Stage II sleep
Cortisol Effects
Metabolism
Glycogen
– Activates glycogen
production\
– Deactivates glycogen
breakdown
Glucose
– Increase hepatic glucose
production
– Inhibits peripheral tissue
utilization of glucose
Lipids
– Activate lipolysis in
adipose tissue
– Redistributes body fat
Sparing of the extremities
Adrenal Insufficiency
Incidence
– 6 cases per 1 million
adults/year
Prevalence
– 40-110 cases per 1 million
adults
More common in females
– 2.6:1
Diagnosed in the 3-5th
decades
Adrenal Insufficiency
Presentation
Signs and symptoms
– Rate and degree of loss
of adrenal function
– Degree of physiologic
stress
– Primary
Mineralocorticoid
deficiency
– Secondary/Tertiary
Mineralocorticoid sufficient
Adrenal Insufficiency
Presentation
Dehydration
Hypotension/shock
– Syncope
Abdominal pain
– Recurrent and unexplained
Mental
status changes
Nausea and vomiting
Weight loss
Fatigue
Hyperpigmentation
Vitiligo
Adrenal Crisis
Presentation
Unexplained hypoglycemia
Hyponatremia
Hyperkalemia
Hypercalcemia
Eosinophilia
Other autoimmune
deficiencies
– Hypothyroid
– Hypogonadal
Adrenal Crisis
Populations at Risk
Secondary adrenal
insufficiency
– Exogenous steroid use
Joint injections
Herbals from Mexico
High dose inhaled steroids
Congenital Adrenal
Hyperplasia
Primary Adrenal Insufficiency
Etiology
Autoimmune
adrenalitis
– 70% of cases
– Polyendocrinopathy-candidiasis-ectodermal dystrophy
(APECED)- PGA I
Autosomal recessive disorder
Mutation in zinc finger protein
Adrenal failure, hypoparathyroidism, mucocutaneous
candidiasis, dental enamel hypoplasia, dystrophy of the nails
Primary Adrenal Insufficiency
Etiology
Autoimmune
adrenalitis
– Polyglandular autoimmune II
Primary adrenal insufficiency, Autoimmune thyroid disease
(hypo and hyper), Type I Diabetes, hypogonadism
Infectious
– Tuberculosis
5% of cases
Rifampin will increase cortisol metabolism-higher dose
needed
– Histoplasmosis
Ketoconazole inhibits steroid synthesis
Primary Adrenal Insufficiency
Etiology
Bilateral
adrenal hemorrhage
– Ill patients on anticoagulants
– Coagulopathies
– Heparin
Thrombosis and thrombocytopenia
– Primary antiphospholipid antibody syndrome
Primary Adrenal Insufficiency
Etiology
Adrenoleukodystrophy
and
adrenomyeloneuropathy
– X-linked
– Defect in β-oxidation
– Mutations in gene encoding a peroxisomal membrane
protein of the ABC superfamily of membrane
transporters
– Demyelination of central and peripheral nervous system
– High levels of very long chain fatty acids (VLCFA)
Primary Adrenal Insufficiency
Etiology
Familial
glucocorticoid Deficiency
– Autosomal recessive
– ACTH resistance
High plasma ACTH concentrations
– Cortisol and androgen deficiency
– Aldosterone is normal
– Presents in childhood
Hyperpigmentation
Muscle weakness
Hypoglycemia and seizures
Low epinephrine
Primary Adrenal Insufficiency
Etiology
HIV/AIDS
– Adrenal necrosis
Infiltrative etiologies
– CMV or TB
Bilateral
metastatic infiltration
– Breast cancer
– Bronchogenic carcinoma
– Renal malignancies
Primary Adrenal Insufficiency
Etiology
Drugs that inhibit cortisol
synthesis
–
–
–
–
–
–
Aminoglutethimide
Etomidate
Ketoconazole
Metyrapone
Suramin
Mitotane
Accelerate cortisol metabolism
– Phenytoin
– Barbituates
– Rifampin
Secondary Adrenal Insufficiency
Etiology
Glucocorticoid use
Pituitary
– Tumors
– Hemorrhage
Pituitary necrosis (Sheehan
Syndrome)
–
–
–
–
Metastatic malignancies
Lymphocytic hypophysitis
Sarcoidosis
Histiocytosis X
Developmental
abnormalities
– Pit-1
– Prop-1
– Septo-optic dysplasia
Adrenal Insufficiency
Diagnosis
Always test for thyroid
sufficiency
Insulin Hypoglycemia test
– Tests anterior pituitary
function
– Insulin 0.15U/kg/body
– Cortisol and growth hormone
drawn at baseline
– Repeat when glucose <35
mg/dl
Contraindicated
– Elderly, CAD, seizures
Adrenal Insufficiency
Diagnosis
Overnight Metyrapone
testing
– Tests for secondary or tertiary
abnormalities
– Blocks 11β-deoxycortisol to
cortisol
– Can initiate adrenal crisis
– Useful in determining return of
function from steroid
suppression
Normal result
Metyrapone is difficult to
obtain
– Increased ACTH
– Increased 11β-deoxycortisol
Adrenal Insufficiency
Diagnosis
Secondary cause
–
–
–
–
– Normal renin-angiotensin system
Normal kalemia
No hyperpigmentation
Baseline critical samples
– Hypoglycemia or hypotension
– Metabolic panel, CBC, Cortisol,
ACTH
– Thyroid function studies
High dose-
250 mcg ACTH
Evaluates primary disease
Critically ill
Inpatient setting
Low dose
– 1 mcg ACTH
– Evaluates primary
Secondary if long standing
Outpatient setting
Evaluating for return of
adrenal function
Steroids
Potency
Steroid
AntiInflammatory
Action
HPA
Suppression
Salt
Retention
Cortisol
1
1
1
Prednisolone
3
4
0.74
Methylprednisolone
6.2
4
0.5
Dexamethasone
26
17
0
Fludrocortisone
12
12
125
Adrenal Crisis
Inpatient Treatment
Fluid resuscitation
– Saline and dextrose
Hydrocortisone
(Solucortef)
– 100 mg IV bolus then
100mg IV Q6hrs
Once stable
Wean hydrocortisone
– 50 mg IV Q6-8hrs
– Taper and transition to
oral therapy
If primary
– Once saline heplocked
– Start Florinef
(fludrocortisone 0.1 mg
PO QD)
Outpatient Treatment
Cortisol
– Hydrocortisone
10mg AM and 5 mg PM
6-8 mg/m2/day
Stress dosing
–
–
–
–
Fever, illness, surgery
20 mg/m2/day
Double or triple daily dose
100 mg x1 then 25-50 mg Q6-8hrs
All adrenal insufficient
patients need a medic alert
bracelet
Outpatient Treatment
Alternative
glucocorticoid replacement
– Dexamethasone 0.5 mg (0.25-0.75) per day
– Prednisone 5 mg (2.5-7.5) per day
Florinef
dosing
– Usual production 100mcg per day
– 0.05-0.2 mg (50-200mcg) per day
