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Transcript of 03.02.10: Adrenal Physiology & Steroid Pharmacology; Disorders of the Adrenal Cortex Adrenal...
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Author(s): Arno Kumagai, M.D., Gary Hammer, M.D., Ph.D., 2009 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution–Noncommercial–Share Alike 3.0 License: !http://creativecommons.org/licenses/by-nc-sa/3.0/ ! We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact [email protected] with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
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Adrenal Physiology & Steroid Pharmacology
Gary D. Hammer, M.D., Ph.D. University of Michigan
Ann Arbor, Michigan USA
Winter 2010
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Learning Objectives
• The feedback loops regulating cortisol secretion.
• The physiologic actions of glucocorticoids (cortisol) + mineralocorticoids (aldosterone)
• The major pharmacologic uses of glucocorticoids.
• The major types of glucocorticoids.
• The major side effects of glucocorticoid therapy.
After this lecture you should have an understanding of:
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Anatomy of the adrenal glands
Wikimedia commons
Gray’s Anatomy, wikimedia commons
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Histology of the Adrenal Gland
adrenal cortex
adrenal medulla
z. glomerulosa z. fasciculata z. reticularis
Sources Undetermined
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Adrenal
Cortisol Aldosterone GLUCOCORTICOID MINERALOCORTICOID
cortex medulla
Adrenocortical Hormones = Steroids
G. Hammer
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Steroidogenesis
reticularis
fasciculata
glomerulosa
gonad periphery
Sources Undetermined
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‘Roids: The Bottom Line
In the right amounts, steroids can be the body’s best friend….
or
in the wrong amounts, the body’s worst enemy….
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Role of Glucocorticoids in Human Physiology
• Your blood pressure up (maintain cardiovascular stability).
• Your blood sugar up (maintain metabolic homeostasis).
• Your disposition sunny (maintain integrity of CNS function).
• Your temperament cool (regulate response to stress).
In the right amounts, glucocorticoids keep:
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Adrenocortical Hormones = Steroids
Adrenal
Cortisol Aldosterone GLUCOCORTICOID MINERALOCORTICOID
cortex medulla
G. Hammer
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Regents of the University of Michigan
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Regulation of ACTH Expression by CRH
Source Undetermined
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Post-translational Processing of POMC in the Normal Pituitary
POMC = Pro-opiomelanocortin!
ACTH!
MSH = Melanocyte stimulating hormone
Source Undetermined
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STEROID BIOSYNTHESIS
CHOLESTEROL ESTER
! CHOLESTEROL
ADENYLATE CYCLASE ACTH
CELL MEMBRANE
ATP 3',5' cAMP
PROTEIN KINASE
POLYSOME
transcription factors
ACTIVE Transcription
factors
ACTH and Steroid Biosynthesis
G. Hammer
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Circadian Rhythm of Cortisol Secretion
day night day night 24 hour period 24 hour period
Plas
ma
Cor
tisol
µg/
100
ml
20
15
10
5
0 8 AM 4 PM 12 MID 8 am 4 PM 12 MID
Highest in morning!
Lowest in evening!Source Undetermined
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Corticosteroid Binding Globulin (CBG)
• Acidic glycoprotein MW 52,000 • Produced in liver, lung, kidney, testes • Regulates delivery of cortisol to tissues
SHBG Grishkovskaya et al, 1999
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Secretion, Transport and Metabolism of Cortisol
Source Undetermined
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Conditions that Affect Cortisol Metabolism
• Increased Turnover: --Thyroxine --Barbiturates
--Phenytoin • Decreased Turnover:
--Liver disease • Increased Binding:
--Estrogens
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Molecular Action of Glucocorticoids
Glucocorticoid receptors (GR) are transcriptional activators of a variety of gene products.
Source Undetermined
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Metabolic Effects of Glucocorticoids
Prototypical Glucocorticoid = Cortisol
Glucocorticoids ! Insulin
Glucocorticoids effects are generally opposite those of insulin.
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Glucocorticoids & Carbohydrate Metabolism
INSULIN (+)
(-) Glucose
GLUCOCORTICOIDS
(+)
(-)
Glucocorticoids increase hepatic glucose output
Glucocorticoids decrease insulin
sensitivity
MUSCLE
FAT CELL
Liver
A. Kumagai
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Glucocorticoid Effects on Protein Metabolism
Insulin
Anabolism (storage) Protein synthesis Protein breakdown Amino acid release
Glucocorticoids
Catabolism Protein synthesis Protein breakdown Amino acid release
MUSCLE
A. Kumagai
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Glucocorticoid Effects on Lipid Metabolism
Insulin
Anabolism (storage) Lipid synthesis Lipolysis Fatty acid release
Glucocorticoids
Catabolism Lipid synthesis Lipolysis Fatty acid release
ADIPOCYTE
Redistribution of fat
A. Kumagai
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Glucocorticoid Effects on Inflammatory Mediators
1) Arachidonic acid and its metabolites (prostaglandins; leukotrienes)
2) Platelet activating factor (PAF) 3) Tumor necrosis factor (TNF)
4) Interleukin-1 (IL-1)
5) Plasminogen activator
Inhibit:
Glucocorticoids INHIBIT inflammation.
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Sites of Action of Glucocorticoids in the Responses of Leukocytes During Antigenic Challenge/Inflammation
Source Undetermined
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Clinical Uses of Glucocorticoids
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Clinical Uses of Glucocorticoids
• Replacement therapy
• Anti-inflammatory effect
• Immunosuppression
• Androgen suppression
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Steroid Therapy: Routes of Administration
• Systemic Oral Parenteral
• Topical • Inhalation
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Emily Janz, a 36-year old woman presents with a 3-year history of rheumatoid arthritis. The disease has been progressive with involvement of PIP joints in both hands, wrists, elbows and TM joints. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) has not been successful.
Treatment with prednisone is begun using an alternate-day program.
Glucocorticoids: Use as Anti-Inflammatory Agents
Severe RA of hands
Source Undetermined
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A 25-year old man was walking through a field when he was stung by an insect. He developed generalized edema, dyspnea, wheezing and dizziness. He was rushed by a friend to the emergency room, where a diagnosis of anaphylactoid reaction to insect bite was made. He received a large dose of steroids parenterally and was subsequently advised on a program to taper the steroids over the next one week.
Glucocorticoids: Use in Immunosuppression
Alvesgaspar, wikimedia commons
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James Allen, a 55-year old man with a history of ischemic cardiomyopathy develops increasingly severe congestive heart failure. When he becomes totally incapacitated with a life-expectancy of less than 6 mo., he is placed on the cardiac transplantation list. Two months later, he receives a heart and is subsequently placed on an immunosuppressive “cocktail” that includes prednisone, 5 mg daily.
Glucocorticoids: Use in Immunosuppression
Heart
A. Kumagai
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Glucocorticoids: Use in Androgen Suppression
A 25-year old woman comes in for evaluation of hirsutism present over the past 3 years. The hirsutism is of the androgen type and is associated with acne and irregular menses. Diagnostic studies reveal elevated serum dehydroepiandrosterone (DHEA) and testosterone levels.
She receives Dexamethasone 2.0 mg daily, for seven days and serum DHEA and testosterone levels are measured the 8th day.
Hirsutism in a young woman Source Undetermined
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Steroidogenesis
reticularis
fasciculata
glomerulosa
gonad periphery
Sources Undetermined
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Adrenocortical Hormones = Steroids
Adrenal
Cortisol Aldosterone GLUCOCORTICOID MINERALOCORTICOID
cortex medulla
G. Hammer
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Effects of Mineralocorticoid on Renal Tubule
Prototypical mineralocorticoid = Aldosterone
Aldosterone increases sodium resorption and potassium and hydrogen ion excretion.
BLOOD URINE
H+ K+ Na+
K+
Na+
(Toilet) weegolo, flickr (Renal tubule pathway) Source Undetermined
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Prototype of Steroid Compounds
Source Undetermined
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Steroids: Structure-function Relationships
A. Hydrocortisone B. Prednisone C. 9-"-Fluorocortisol
• Double-bond in 1,2 position increases glucocorticoid activity. • Fluoro- group in 9-a position increases mineralocorticoid activity.
Source Undetermined
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Steroids
Compound Anti-Inflam. potency
Na-Retain. potency
Duration of action
Equivalent Dose
Cortisol 1 1 Short 20 mg
Prednisone 4 0.8 Intermediate 5 mg
9-"-fluoro-cortisone
10 125 Short *
Dexa-methasone
25 0 Long 0.75 mg
Glucocorticoid effects: Dex > Prednisone > Cortisol
Mineralocorticoids: 9-"-fluorocortisone RULES G. Hammer
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Glucocorticoid Therapy
Side Effects
Or
“Yes, Virginia, there can be at times ‘Too Much of a Good Thing…’”
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Glucocorticoid Effects on Calcium & Bone
! Osteoblastic activity ! Calcium absorption from gut. # PTH secretion # Osteoclastic activity
STEROIDS “BRITTLE BONES”
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A 60 yo postmenopausal woman was seen in clinic with acute onset of mid-thoracic back pain. She had complained of back pain for the past 2 years and a 2” loss of height. She had been on Prednisone, 10-15 mg daily, for the past 5 years for chronic polymyositis. Radiographic exam of the spine shows compression deformities in several vertebral bodies.
Steroids “Brittle Bones”
CC:BY-NC-ND 2.0 UK Medical Art Service, wellcome images
Source Undetermined
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Chronic Glucocorticoid Therapy & Carbohydrate Metabolism
BLOOD GLUCOSE
GLUCOCORTICOIDS
(+)
(-)
INSULIN (+)
(-)
Chronic glucocorticoid therapy may “unmask” diabetes in genetically susceptible individuals.
MUSCLE
FAT CELL
Liver
A. Kumagai
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Glucocorticoid Effects on the Central Nervous System
• Neuronal death or atrophy • Structures affected: Hippocampus, caudate • Neuropsychiatric symptoms:
- Cognitive- memory, learning - Mood- irritability, depression - Sleep- insomnia
Caudate
Hippocampus CC:BY-NC-ND 2.0 UK Medical Art Service, wellcome images
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A 42-yo woman with an exacerbation of lupus nephritis was treated with high-dose prednisone for several days. Her nephritis improved markedly; however, she became increasingly euphoric and severely agitated with paranoid ideation and confusion. Following tapering of the steroid, she returned to her “usual self.”
“Steroid Psychosis”
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Glucocorticoid Effect on Gastric Function
• # Secretion of HCl and pepsin • ! Protective barrier in the gastric mucosa
STOMACH
Glucocorticoid therapy may increase risk of ulcers.
A. Kumagai
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Complications of Chronic Exogenous Corticosteroid Use
CRH
ACTH
Adrenal Gland
Cortisol
Hypothalamus
Pituitary
(+)
(-)
(-)
G. Hammer
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Complications of Chronic Exogenous Corticosteroid Use
CRH
ACTH
Adrenal Gland
Cortisol
Hypothalamus
Pituitary
Exogenous Glucocorticoid (-)
(+) Exogenous glucocorticoids suppress ACTH-
stimulated cortisol secretion.
G. Hammer
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Complications of Chronic Exogenous Corticosteroid Use
CRH
ACTH
Adrenal Gland
Cortisol
Hypothalamus
Pituitary
(-)
(+) High-dose, long-term
glucocorticoid use results in adrenal
atrophy from ACTH suppression
ACTH is normally a trophic factor for the
adrenals
Exogenous Glucocorticoid
G. Hammer
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Complications of Chronic Exogenous Corticosteroid Use
CRH
ACTH
Adrenal Gland
Cortisol
Hypothalamus
Pituitary
(+)
Adrenal Insufficiency
Exogenous Glucocorticoid
G. Hammer
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Complications with Prolonged Corticosteroid Therapy
• Retarded longitudinal growth in children*
• GI Bleeding • Osteoporosis* • Diabetes* • Cushing’s Syndrome
• Steroid myopathy • Hypertension • Cataracts • Psychiatric • Adrenal suppression*
*Complications to remember
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12
HIGH RANGE
NORMAL RANGE
LOW RANGE
months 4 6 8 10 2
Phase 1 Phase 2 Phase 3
ACTH
Recovery of Endogenous Cortisol Secretion Following Withdrawal of Exogenous Steroids
Full recovery of endogenous cortisol secretion may require up to 18 months following steroid withdrawal.
Source Undetermined
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Case #1
A 45-year old woman present with a two-month history of anorexia, nausea, fatigue, dizziness when assuming the upright posture, and increased pigmentation of the skin.
A diagnosis of Addison’s disease (Cortisol and Aldosterone deficiency) is confirmed by appropriate testing. Treatment is initiated with Cortef 25 mg. (10/10/5) and 9-" fluorocortisol 0.05 mg QD.
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Corticosteroid Therapy Considerations
• How serious is the underlying disorder?
• How long is therapy required?
• What is the anticipated effective dose range?
• Is patient predisposed to complications?
• Which preparation to use?
• Alternate day vs every day therapy.
• Program for withdrawal.
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Things to Remember if I put you to sleep and you’re just waking up…:
• Feedback loops regulating cortisol secretion.
• The major physiologic actions of glucocorticoids (cortisol) and mineralocorticoids (aldosterone).
• The major pharmacologic uses of glucocorticoids.
• The major types of glucocorticoids--hydrocortisone, prednisone, dexamethasone, 9-a-fluorocortisol.
• The major side effects of glucocorticoid therapy.
Understand:
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Adrenal Steroid Physiology & Pharmacology
Questions?
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Disorders of the Adrenal Cortex
Gary D. Hammer, M.D., Ph.D. University of Michigan
Ann Arbor, Michigan USA
Winter 2009
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Goals/Objectives
! Remember the basic principles of the HPA axis: homeostatic control of plasma cortisol and aldosterone levels
! Remember the mechanism of action of glucocorticoids and mineralocorticoids
! Understand etiology, clinical features, differential diagnosis, evaluation and therapy of 3 classic adrenal disorders:
! Adrenal Insufficiency ! Cushing’s Syndrome ! Primary Hyperaldosteronism
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Which Twin is Sick????
N Engl J Med 1997;337:1666.
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Adrenal Glands in Medical History
Andreas Vesalius (1543) Book Five of De Corporis Humani Fabrica in 1543
Bartholomäus Eustachius (1564) glandulae quae renibus incumbent" in 1564
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History of Adrenal
! 1716: Academie des Sciences of Bordeaux poses the question "Quel est l'usage des glandes surrenales?"
! 1845: French thesis on organs of unknown function "The adrenal cease(s) to be a secreting gland."
! 1855: Thomas Addison monograph “On the constitutional and local effects of disease of the supra-renal capsules,” described 10 cases marked by "anemia . . . feebleness of the heart action . . . a peculiar change of color in the skin occurring in connection with a diseased condition of the ‘suprarenal capsules'.
! In 1945 Nobel Prize Kendall, Pfiffner, and Reichenstein first tested adrenal extracts on a patient with Addison's disease, and the response was prompt and striking.
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Anatomy of the adrenal glands
Gray’s Anatomy, wikimedia commons
Wikimedia commons
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Histology of the Adrenal Gland
adrenal cortex
adrenal medulla
z. glomerulosa z. fasciculata z. reticularis
Sources Undetermined
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Adrenocortical Hormones = Steroids
Adrenal
Cortisol! Aldosterone!GLUCOCORTICOID! MINERALOCORTICOID!
cortex!medulla!
G. Hammer
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Definition of Adrenal Insufficiency
! “inappropriately low” adrenal steroid output
! mineralocorticoids (aldosterone) ! glucocorticoids (cortisol) ! sex steroids (DHEAS)
G. Hammer
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How Frequent Is Adrenal Insufficiency?
! In general, about 40-60 per million individuals have adrenal insufficiency ! 30,000-34,000 people in U.S.
inoc, flickr
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Types of Adrenal Insufficiency
Cortisol
CRH
ACTH
Adrenal Gland
Hypothalamus
Pituitary
(+)
(-)
(-)
PRIMARY
SECONDARY
TERTIARY
G. Hammer
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Adrenal Insufficiency
hypothalamic CRH
pitui tary ACTH
adrenal cortisol
adrenaldefect
1ºadrenal insufficiency
pitui tarydefect
2ºadrenal insufficiency
hypothalamicdefect
2ºadrenal insufficiency
+
+
-
-
adrenal aldosterone
Source Undetermined
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Adrenal Insufficiency: Age Dependent Prevalence
mean age 40 yo (range 17-72 yo)
adults and elderly: glucocorticoids for non -adrenal diseases
young men: adrenoleukodystrophy
children: consider PGA or genetic defect
autoimmune adrenalitis most common in all age groups
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PRIMARY Adrenal Insufficiency
Cortisol
CRH
ACTH
Adrenal Gland
Hypothalamus
Pituitary
(+)
(-)
(-)
PRIMARY
G. Hammer
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PRIMARY Adrenal Insufficiency
! Autoimmune adrenalitis (PGA I or II) 80% ! Infections: TB (20% - historically), CMV, fungal ! Vascular: hemorrhage, thrombosis, arteritis
! In cancer patients: metastatic cancer to adrenals ! In young men: adrenoleukdystrophy
Cortisol
CRH
ACTH
Adrenal Gland
Hypothalamus
Pituitary
(+)
(-) (-)
Aldosterone
IMPORTANT: In PRIMARY adrenal insufficiency, the adrenals are destroyed, and ALDOSTERONE is affected as well.
Thomas Addison (1793-1860)!
G. Hammer
Source Undetermined
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Adrenal Tuberculosis
Adrenal atrophy
Normal adrenal
Autoimmune Adrenalitis
Adrenal Hemorrhage
PRIMARY Adrenal Insufficiency
Sources Undetermined
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Metastases in the Adrenal Gland
• Lung • Kidney • Ovaries • Skin • Chest • Leukemia • Lymphomas
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Adrenoleukodystrophy/Adrenomyeloneuropathy
X-LINKED - ONLY IN MALES PRESENTATION -adrenal insufficiency (childhood) -hypergonadotropic hypogonadism (puberty) -spastic paraparesis/demyelination-AMN(20-30 yo) vs cerebral sclerosis-ALD (childhood)
PATHOPHYSIOLOGY: mutation in Adrenoleukodystrophy protein(ALPD) ALPD function -pexoxisomal transport protein anchors very long chain AcylCoA synthetase
DISEASE - build up of chol. esters w unbranched saturated long chain FAs TREATMENT: Cortisol replacement
Lorenzo’s Oil helps serum level of VLCFA - but no clinical benefit in 3 yr F/U
MUST BE INCLUDED IN w/u of AI in young men and in w/u AI or hypoglycemia in infants
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Adrenal atrophy
Normal adrenal
PRIMARYAdrenal Insufficiency
Autoimmune adrenalitis results in ADRENAL INSUFFICIENCY
Autoimmune adrenalitis (and therefore its subsequent ADRENAL INSUFFICIENCY) can be found in specific genetic syndromes, POLYGLANDULAR AUTOIMMUNE SYNDROMES
Source Undetermined
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PRIMARYAdrenal Insufficiency
2 of the following ! adrenal insufficiency (<15 yo) ! hypoparathyroidism (<10yo) ! chronic mucocutaneous candidiasis (<5 yo)
! PLUS OFTEN ! dental enamel hypoplasia ! keratopathy/ecdodermal dystrophy
PGA I (Polyglandular Autoimmune Syndrome I) autosomal recessive disease- Iranian Jewish heritage starting in childhood
APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy)
autosomal recessive-Finnish heritage starting in childhood
occasionally ! chronic active HepB ! malabsorption ! cholelithiosis ! juvenile onset pernicious anemia
! alopecia/vitiligo ! primary hypogonadism ! hypothyroidism ! diabetes mellitus
AIRE (AutoImmune REgulator) Nat Gen 17: 393398; 399-403
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Which Twin is Sick????
N Engl J Med 1997;337:1666.
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Famous Names in Endocrinology
Addison’s Disease
Jane Austin (1775-1817) John F. Kennedy Cassandra Austen (c. 1810) Cecil Stoughton, White House
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Addison’s Disease & History
1960 Presidential Debate John F. Kennedy vs. Richard M. Nixon
Chicago, Ill., September 21, 1960
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! PGA II ! usually in middle age females ! adrenal insufficiency ! hyothyroidism or diabetes mellitus
! *uncertain genetic component ! autosomal dominant more likely ! HAL-B8 chromosome 6
! PGA III ! hypothyroidism ! other autoimmune disorder (NOT adrenal insufficiency)
Adrenal Insufficiency
Autoimmune adrenalitis
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PRIMARYAdrenal Insufficiency!
Cortisol!
CRH!
ACTH!
Adrenal Gland!
Hypothalamus!
Pituitary!
(+)!
(-)!(-)!
Aldosterone!
SIGNS • Proximal muscle weakness • Orthostatic hypotension • HYPERPIGMENTATION--Primary AI only • HypoNa, HyperK—Primary AI only
SYMPTOMS Cortisol
• Fatigue • Weakness & Malaise • Anorexia • Nausea and vomiting
Aldosterone
• Dizziness
G. Hammer
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Hypotension Hyperkalemia Hyponatremia
Hypoaldosteronism
pregnenolone
aldosterone
18OHCS
CS DOCS progesterone
cholesterol
p450scc sTaR
3ßHSD p450c11B2
p450c21
p450c11B2 - 18 ßHSD
p450c11B2 - 18 OH
G. Hammer
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PRIMARY Adrenal Insufficiency (ALDOSTERONE DEFECT ONLY SEEN IN PRIMARY AI not SECONDARY AI)
Na+!K+!
Cl-!HCO3
-!Glu!
Aldosterone increases sodium
resorption and potassium and hydrogen ion
excretion.!
H+!
K+!Na+!
K+!Na+!
RENAL TUBULE! BLOOD!
ALDOSTERONE!
So, with aldosterone deficiency:!Source Undetermined
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hypotension
fatigue
hypoglycemia
Glucocorticoid Deficiency
17OHPregnenolone
pregnenolone
cortisol DOC
progesterone
17OHprogesterone
cholesterol
p450scc
17 OH
sTaR
p 4 5 0
c 1 7
3ßHSD
3ßHSD p450c11B1 p450c21 17 OH
G. Hammer
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DHEAS Deficiency
Female: fatigue, ! mood, libidinal dysfunction Male: fatigue, ! mood
17OHPregnenolone
pregnenolone progesterone
androstenedione
17OHprogesterone
DHEA
cholesterol
p450scc
17 OH
17,20lyase
sTaR
p 4 5 0
c 1 7
3ßHSD
3ßHSD
3ßHSD
17 OH
17,20lyase
sulfotransferase
DHEAS
sulfatase
G. Hammer
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Adrenal Insufficiency: Hyperpigmentation
Hyperpigmentation of palmar creases
ACTH!
$-MSH%
Source Undetermined
Source Undetermined
N Engl J Med 1997;337:1666.
T. Addison “On the constitutional and local effects of disease of the suprarenal capsules” 1855
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SECONDARY Adrenal Insufficiency!
CRH!
ACTH!
Adrenal Gland!
Hypothalamus!
Pituitary!
(+)!
(-)!
(-)! SECONDARY!
Cortisol!
G. Hammer
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TERTIARY Adrenal Insufficiency
CRH
ACTH
Adrenal Gland
Hypothalamus
Pituitary
(+)
(-)
(-)
TERTIARY
Cortisol
G. Hammer
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SECONDARY and TERTIARY Adrenal Insufficiency!
Cortisol!
CRH!
ACTH!
Adrenal Gland!
Hypothalamus!
Pituitary!
(+)!
(-)!
(-)!
! Vascular: Postpartum necrosis(Sheehan’s) ! Lymphocytic hypophysitis ! Infiltrative diseases: Sarcoidosis, Histiocytosis X ! Tumor compression ! Following surgery or radiation ! Long term glucocorticoid treatment Pharmacologic Dose = more than physiologic replacement
G. Hammer
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SECONDARY Adrenal Insufficiency
Cortisol!
CRH!
ACTH!
Adrenal Gland!
Hypothalamus!
Pituitary!
(+)!
(-)!(-)!
Aldosterone!
SYMPTOMS • Mild malaise, fatigue • Proximal muscle weakness
SIGNS • NO hyperpigmentation • NO orthostatic hypotension
SIGNS & SYMPTOMS are generally milder than with primary adrenal insufficiency due to cortisol deficiency ALONE (ie: NO ALDOSTERONE DEFICIENCY)
G. Hammer
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Adrenal Insufficiency
REMEMBER TO DIFFERENCE BETWEEN PRIMARY AI AND SECONDARY AI
SECONDARY ONLY PRIMARY ONLY
associated features (ie can see if PGA)
! vitiligo (4%) ! hypothyroidism (primary) ! hypogonadism (primary)
associated features (ie can see if entire pit. involved)
! growth delay ! HA
! DI (if stalk involved) ! hypothyroidism (secondary) ! hypogonadism (secondary)
! hyperpigmentation (92-96%) ! HYPERkalemia (52-64%)
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Adrenal Crisis
*hemorrhage ! thromboembolic disease ! Coagulopathy ! anticoagulant therapy ! Waterhouse-Friderichsen Syndrome
! Neisseria meningitidis septicemia ! Streptococcus pneumoniae, ! Pseudomonas aeruginosa ! Staphylococcus aureus ! Escherichia coli ! Haemophilus influenzae
! *drugs - increase metabolism GC ! phenytoin, phenobarbitol, rifampin
! *drugs - decrease production GC ! ketoconazole, AG, mitotane, metyrapone
! *withdrawal of exogenous glucocorticoids
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If the diagnosis is missed, your patient will most likely die
! suspect in setting of: ! catecholamine resistant hypotension ! hypotension with abd pain ! must r/o adrenal hemorrhage
! look for: ! hyperpigmentation/decreased pubic hair ! hyperkalemia ! hyponatremia ! hypoglycemia
Adrenal Crisis
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SCREENING TEST: AM CORTISOL: GOAL is to RULE OUT disease Principle of test: Cortisol is highest in the AM allowing maximal chance of ruling out disease
-HI AM cortisol RULES OUT DISEASE
-BUT ONLY EXTREMELY LOW AM cortisol is DIAGNOSTIC Most patients are neither EXTREMELY HI or EXTREMELY LOW and require DYMANIC testing
Adrenal Insufficiency Diagnostic
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Adrenal Insufficiency Diagnostic
DIAGNOSTIC TEST FOR PRIMARY ADRENAL INSUFFICIENCY: ACTH STIMULATION TEST: GOAL is to RULE IN disease Principle of test: ACTH stimulates steroidogenesis and secretion of cortisol - normal levels
well documented
-Cortisol level after ACTH that is SUBNORMAL is DIAGNOSTIC of AI
-ACTH level that is EXTREMELY HI is CONSISTENT with diagnosis of PRIMARY AI but is NOT DIAGNOSTIC
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The ACTH Stimulation Test!
Synthetic ACTH (Cosyntropin)!
Cortisol!
CRH!
ACTH!
Adrenal Gland!
Hypothalamus!
Pituitary!
(+)!
NORMAL!
(-)!
(-)!
ADRENAL INSUFFICIENCY!
Adrenal Gland!
CRH!
ACTH!
Low serum cortisol!
Hypothalamus!
Pituitary!
(+)!
Cortisol! No or blunted
increase in serum cortisol!
G. Hammer
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Adrenal Insufficiency Diagnostic
DIAGNOSTIC TEST FOR SECONDARY ADRENAL INSUFFICIENCY: INSULIN HYPOGLYCEMIA TEST: GOAL is to RULE IN disease Principle of test: Insulin results in hypoglycemia that is the strongest stimulus for activation of HPA axis at the level of CRH
Cortisol level after IHT that is SUBNORMAL is DIAGNOSTIC of AI
ACTH level after IHT that is SUBNORMAL is DIAGNOSTIC of SECONDARY AI
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Diagnosis of Secondary/Tertiary Adrenal Insufficiency
CRH
ACTH
Adrenal Gland
Hypothalamus
Pituitary
(+)
(-)
(-)
Cortisol
The Insulin Tolerance Test
INSULIN
Insulin-induced hypoglycemia is a powerful stimulus of the
HPA axis
G. Hammer
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Therapy for Adrenal Insufficiency
therapy
1543 1564
(Left) Andreas Vesalius (1543) Book Five of De Corporis Humani Fabrica in 1543
(Right) Bartholomäus Eustachius (1564) glandulae quae renibus incumbent" in 1564 (Center Images) Source Undetermined
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Acute Therapy (significant ill or Adrenal Crisis) IV fluids IV cortisol: HI DOSE glucose treat underlying precipitating events Maintenance Therapy Glucocorticoids
hydrocortisone ~ 15-25 mg/d titrate to a sense of well being and physical strength avoid weight gain, hypertension, hyperglycemia and osteoporosis
Mineralocorticoids fludrocortsone ~0.1 mg/d titrate to salt craving and postural hypotension together with serum K and upper range renin
DHEA -
Guidelines for Management
Do not wait for labs!!!!
GUIDING PRINCIPLE: The more severe the stress the more cortisol patient needs!
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Stress Dosing Glucocorticoids Minimal no need for supplemental coverage dental work mild or non-febrile illness
Minor 25 mg hydrocortisone - day of procedure (or onset of fever) hernia repair Moderate 50-75 mg hydrocortisone - day of procedure (or onset of fever) hemicolectomy rapid taper in 1-2 days significant febrile illness Severe 100-150 mg hydrocortisone - day of procedure (or onset of fever) cardiac surgery rapid taper in 1-2 days Critically ill 100 mg hydrocortisone i.v. bolus followed by - sepsis 50-100 mg hydrocortisone i.v. q 6-8 hours (or 0.18 mg/kg/hr)
0.05 mg/d fludrocortisone until shock resolves (days to week)
Guidelines for Management
GUIDING PRINCIPLE: The more severe the stress the more cortisol patient needs!
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Discontinuing Glucocorticoids Following Long Term Suppression
GUIDING PRINCIPLE: The more glucocorticoid and the longer treated - the greater chance of long term suppression and atrophy of HPA axis
risk of suppression Low risk: Low dose, short duration or short “bursts” of glucocorticoid High dose and prolonged therapy (" 1-4 weeks) - risk is higher time course for recovery Larger doses for prolonged periods (months - years) - recovery can take from 9 MONTHS up to 1-2 years need for taper taper from pharmacologic to physiologic (determined by non-adrenal disease course) taper from physiologic to no treatment (determined by adrenal suppression)
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DHEA: What is all the fuss?
! Marker of aging
-??pharmacologic reversal of aging process??
! Predictor of morbidity/mortality
! Works wonders in rodents -CNS, obesity, diabetes, immunity
! Preliminary studies in humans
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DHEA what is it??
! Synthesized by adrenals only in humans and higher primates
-obligate precursor of all sex steroids in humans
! More synthesized than all other steroids -up to 25 mg/day in adults -major secretion of fetal adrenal
! Most secreted as sulfate (DHEA-S) -sulfation is ONLY in ADRENAL (NOT GONAD)
! Inactive at androgen receptor
19 carbon (androstane) &5,3'-hydroxy,17-keto S04, ester at 3'
Source Undetermined
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DHEA: How Does it Work?
! Conversion to androgens
-50 mg/d raises testosterone in females
! Intrinsic activity of DHEA-S in brain -trophic effects on cultured neurons
-GABA, NMDA, sigma receptor-channels
! Actions of weird metabolites -concept of NEUROSTEROIDS
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Case for DHEAS
DHEA + DHEAS major secretory products of adrenal
peak in fetal life and adrenarche
Decline throughout adult life to 20-20% by 70-80 yo
Advertisement as ANTI-AGING drug In USA : FOOD SUPPLEMENT!!!!!
classic steroid converted to testosterone peripherally neurosteroid directly binding NMDA + GABA receptors
TRENDS in Endocrinology & Metabolism
Source Undetermined
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DHEA replacement in women with adrenal insufficiency improved overall well-being and mood, specifically depression, anxiety and both sexual interest and sexual satisfaction.
DHEA in men and women with primary adrenal insufficiency improves mood and well-being, irrespective of the patient's sex.
Case for DHEAS
(Both images) TRENDS in Endocrinology & Metabolism
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Adrenal Androgens only in pts w AI who do NOT feel “normal on replacement GC and MC”
DHEA: 25 mg po q a.m. -may increase to 50 mg -dictated by response and androgenic side effects -monitor labs DHEAS, androstendione and free test LFTS and lipids at 4 + 12 w
Guidelines for DHEA Treatment in Adrenal insufficiency
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Watch Out for Supplements
Steroids are lipophilic unknown dosing unknown purity
Images of steroid supplements comparison
removed
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Adrenal Pathophysiology
Gary D. Hammer, M.D., Ph.D. University of Michigan
Ann Arbor, Michigan USA
Winter 2010
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Adrenal Excess States
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Congenital Adrenal Hyperplasia
Hypothalamus
Cortisol
CRH
ACTH
Adrenal Gland
Pituitary
(+)
(-)
(-)
• Genetic block in biosynthetic pathway for cortisol and aldosterone result in primary adrenal insufficiency.
• Decreased feedback on hypothalamus and pituitary increase CRH and ACTH.
• Increased ACTH further stimulates adrenals and results in shunting and production of precursors.
• ACTH stimulates growth (HYPERPLASIA) of adrenals.
G. Hammer
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Steroidogenesis
reticularis
fasciculata
glomerulosa
gonad periphery
Sources Undetermined
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Steroidogenesis
reticularis
fasciculata
glomerulosa
gonad periphery
Sources Undetermined
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Steroidogenesis
reticularis
fasciculata
glomerulosa
gonad periphery
Sources Undetermined
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SEVERE P45c21 Deficiency in FEMALE
results in androgen excess in utero Source Undetermined
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Sideburns
Beard
Chest Hair Cliteromegaly
Hirsuitism
MILD P45c21 Deficiency in FEMALE
results in androgen excess at puberty Sources Undetermined
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Congenital Adrenal Hyperplasia
• Loss of function of enzyme in steroidogenesis pathway
• “Block” in pathway leads to shunting down alternate paths and abnormal build-up precursors before the block.
• Severe forms lead to virulization of females
• Milder forms (“non-classical”) may lead to hirsuitism and menstrual abnormalities in women.
• Block in pathway may result in adrenal insufficiency during times of stress.
Important things to remember:!
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Causes of hypercortisolism
! Pathologic states ! Cushing's syndrome ! Diabetes mellitus ! Hyperthyroidism ! Severe chronic disease ! Glucocorticoid resistance ! Psychological states ! Anorexia nervosa ! Panic disorder ! Melancholic depression ! Obsessive-compulsive disorder
! PHARMACOLOGIC USE OF GLUCOCORTICOIDS
! Physiological states • Pregnancy • Stress • Chronic excessive exercise • Malnutrition
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Cushing’s Syndrome
Harvey Cushing (far left) in 1895 during his H o u s e P u p i l s h i p ( i n t e r n s h i p ) a t Massachusetts General Hospital.
DR. HARVEY WILLIAMS CUSHING (1869-1939)
Cushing HW. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bulletin of the Johns Hopkins Hospital. 1932;50:137-95 His research on the pituitary body gained him an international reputation, and he was the first to ascribe to pituitary malfunction a type of obesity of the face and trunk now known as Cushing's disease, or Cushing's syndrome.
Dr. Zak, wikimedia commons Source Undetermined
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! All types of Cushing’s Syndrome ! HI CORTISOL (urine and serum) ! Absent circadian rhythm
! Adrenal Cushing’s syndrome is autonomous and therefore has LOW ACTH ! Only ACTH-dependent Cushing’s (by definition) has HI ACTH
Cushing‘s Syndrome
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Cushing’s Syndrome
hypothalamic CRH
pituitary ACTH
adrenal cortisol
adrenaldefect
adrenal Cushing‘s
pituitarydefect
ACTH dependent Cushing‘s
ectopic defect
+
+
-
-
ectopic ACTH
Cushing‘s
ectopic CRH
Cushing‘s
ectopicACTH
ectopicCRH
pituitary ACTH
Cushing‘s
ACTH independent !Cushing’s !
Source Undetermined
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Cushing’s Syndrome
Exogenous GC administration!
Endogenous hypercortisolism!
ACTH-dependent!
ACTH-independent!
Pituitary adenoma!
Ectopic ACTH (CRH) syndrome!
Adrenal adenoma!
Adrenal carcinoma!
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all result in bilateral adrenal hyperplasia
! ACTH-dependent Cushing’s Syndrome
! pituitary adenoma-ACTH (60%) ! Ectopic hormone (10%) ! ACTH ! CRH
Cushing’s Syndrome
Source Undetermined
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Types of Cushing’s Syndrome
Cortisol
CRH
ACTH
Adrenal Gland
Hypothalamus
Pituitary
(+)
(-)
(-)
PITUITARY ADENOMA
Cushing’s Disease (“pituitary Cushings”): hypercortisolism from a
pituitary adenoma HARVEY
G. Hammer
Dr. Zak, wikimedia commons
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Normal Pituitary
Source Undetermined Source Undetermined
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Pituitary Cushing‘s DISEASE
normal Cushing’s disease
Source Undetermined Source Undetermined
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Ectopic Cushing’s
CRH
ACTH
Adrenals
Hypothalamus
Pituitary (-)
(-)
Cortisol
Hypercortisolism from Ectopic production of
ACTH or CRH by tumor.
ACTH Causes • Bronchial carcinoid • Oat cell carcinoma • Thymic carcinoid • Pheochromocytoma • Medullary thyroid ca Small (Oat) cell ca of lung
(Lungs) Source Undetermined
(Other images) G. Hammer
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! ACTH-independent Cushing’s Syndrome ! adrenal cortical neoplasm
! adenoma ! carcinoma
! primary adrenal hyperplasia
Cushing’s Syndrome
Source Undetermined
Source Undetermined
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Adrenal Cushing’s
CRH
ACTH
Adrenal
Hypothalamus
Pituitary
(+)
(-)
(-)
Cortisol
Adrenal Causes: Hypercortisolism from a
adrenal adenoma or carcinoma
Contralateral Adrenal
Because ACTH is suppressed, the rest of the adrenal and contralateral
gland are atrophied.
Adrenal adenoma or carcinoma
G. Hammer
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Cushing’s Syndrome
CLINICAL MANIFESTATIONS of CORTISOL EXCESS
! increased protein catabolism = striae, bruising, delayed wound healing, muscle wasting
! increased glucose production = DM
! redistribution of fat = truncal obesity
! bone breakdown = osteoporosis
! facilitation of catechol synthesis = hypertension
! anti-inflammatory = opportunistic infections
! Inhibition of HPG axis = amenorrhea, impotence
! CNS effects(limbic/hippocampus) = depression and memory difficulties
ACTH dependent ONLY ! Pigmentation (MSH)
ACTH dependent or Mixed Adrenal ! Androgen excess
! Terminal hair hirsuitism ! Acne ! Irregular menses ! balding
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Cushing‘s Syndrome
! Physical examination: ! adiposity ! moon face, plethora ! (pseudo-) gynecomastia ! striae
Source Undetermined Source Undetermined
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Redistribution of Fat in Glucocorticoid Excess
Central obesity seen in Cushing’s Syndrome (Glucocorticoid Excess)
Source Undetermined
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Cushing‘s Syndrome
! Acanthosis nigricans ! Purple striae
Source Undetermined Source Undetermined
Source Undetermined
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! Myopathy ! Proximal muscle wasting
! Osteoporosis ! Oligo-Amenorrhea/Impotence ! Psychiatric Symptoms
! depression, mania (Steroid psychoses)
Cushing‘s Syndrome
Sources Undetermined
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ACTH-Dependent Pituitary Cushing‘s Disease
! Symptoms due to pituitary mass ! bitemporal hemianopsia ! pituitary insufficiency ! HA
Source Undetermined
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! Diagnosis ! First diagnose CORTISOL EXCESS ! elevated 24 hr urine cortisol < 100 mg/24 hr
! Then diagnose PATHOLOGIC CORTISOL EXCESS ! r/o physiologic causes which suppress normally with low-dose DEX (Cort < 2 mg/dl)
! ACTH dependent or NOT ! Measure ACTH level
! if DETECTABLE > 9 pg/ml - must be ACTH dependent ! (if NOT DETECTABLE < 9 pg/ml - must be ACTH independent)
Cushing‘s Syndrome: Diagnosis
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Cushing’s Syndrome: Low-dose DEX suppression
CRH
ACTH
Adrenal Gland
Hypothalamus
Pituitary
(+)
(-)
(-)
Low-Dose DEX
Cortisol ACTH
Ectopic tumor
ACTH
Low-dose Dex will suppress ACTH secretion in: -normal patients -physiologic hypercortisolism (stress) Low-dose Dex will NOT suppress ACTH secretion in: !-ACTH dependent Cushing’s syndrome (pituitary adenoma or ectopic ACTH producing tumors) -ACTH independent Cushing’s syndrome (adrenal tumors)
G. Hammer
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! High dose DEX SUPPRESSION TEST ! Pituitary Cushing’s may suppress to high dose DEX ! Ectopic NEVER suppresses to high dose DEX
! Inferior Petrosal sinus Sampling ! Pituitary Cushing’s - find HI ACTH near pituitary and low in the periphery ! Ectopic Cushing’s - find HI ACTH in the periphery and low near pituitary
! IMAGE the pituitary
ACTH-DEPENDENT Cushing’s Syndrome
Is it pituitary or ectopic????
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Cushing’s Syndrome: Hig-dose DEX suppression
CRH
ACTH
Adrenal Gland
Hypothalamus
Pituitary
(+)
(-)
(-)
HIGH-Dose DEX
Cortisol ACTH
High-dose Dex will suppress ACTH secretion in: -ACTH dependent Cushing’s syndrome (pituitary adenoma) High-dose Dex will NOT suppress ACTH secretion in: !-ACTH dependent Cushing’s syndrome (ectopic tumors)
Most pituitary adenomas that secrete ACTH can still be inhibited by REALLY REALLY HIGH glucocorticoids (ie more that produced their diseased HPA axis) Therefore, HIGH-dose dexamethasone will NOT suppress ACTH from ectopic tumors.
G. Hammer
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Cushing’s Syndrome: Diagnosis
CRH
ACTH
Adrenal Gland
Hypothalamus
Pituitary
(+)
(-)
(-)
HIGH-Dose DEX
Cortisol Ectopic tumor
ACTH
Most ectopic ACTH-producing tumors secrete ACTH independently from regulation by glucocorticoids. Therefore, HIGH-dose dexamethasone will NOT suppress ACTH from ectopic tumors.
High-dose Dex will suppress ACTH secretion in: -ACTH dependent Cushing’s syndrome (pituitary adenoma) High-dose Dex will NOT suppress ACTH secretion in: -ACTH dependent Cushing’s syndrome (ectopic tumors)
G. Hammer
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Imaging in Cushing Syndrome
! ADRENAL CT findings ! adrenals small = ? ! one adrenal large and 1 small =? ! Both adrenals large=?
! Pit MRI findings ! Mass or no mass
(some pituitary corticotrope tumors are too small to be seen on MRI)
! Search for ectopic ACTH or CRH producing tumor ! Lung: Bronchial Carcinoid and SCC 50% ! Thymic Carcinoid (epithelial thymoma 10% ! Pancreatic Islet Cell Tumor 10% ! Pleochromocytoma 10% ! Abdominal Carcinoids 5% ! Medullary Thyroid Carcinoma 5%
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Cushing’s Syndrome Treatment
! adrenal adenoma ! resection ! cortisol replacement ! if not curative
! XRT ! bilateral adrenalectomy ! adrenolytic therapy
! mitotane ! ketoconazole
! pituitary adenoma ! transphenoidal resection (TSR) ! cortisol replacement ! if not curative
! XRT ! bilateral adrenalectomy ! adrenolytic therapy
! mitotane ! ketoconazole
! Ectopic ACTH or CRH ! Find the tumor!!!!!!!!!!! ! if not curative
! bilateral adrenalectomy ! adrenolytic therapy ! mitotane ! ketoconazole
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Cushing‘s Syndrome
before treatment
after treatment
Sources Undetermined
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Cushing‘s Syndrome
ferrets dogs
horses
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UM Endocrinology in Adrenal History: Conn Syndrome
Jerome Conn, M.D. Source Undetermined Source Undetermined
Image of Jerome Conn, M.D. removed
Conn JW. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45:3-17
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Primary Aldosteronism
! Clinical Presentation ! Manifestations of HYPOKALEMIA and HTN ! LOW K ! neuromuscular ! paresthesias ! weakness ! tetany
! Renal ! Polyuria
! Carbohydrate ! abnormal GTT
! HTN usually not malignant ! early in disease may have HTN with NORMAL K
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-constitutive MR or Na channel
-ADRENAL overproduction of ALDO
-overproduction of AII by renal tumors
-ACE polymorphisms
-JGA renin tumor
Causes of Hyperaldosteronism
Definition: syndrome of inappropriate excessive secretion of aldosterone by adrenal gland
renin
IVV
liverangiot ensinogen angiot ensin angiot ensin II
AC E
kidney(JGA)
lung
++
++
---->adrenal
(glomer ulosa )
aldosteroneIVV
met alkK (serum)
HK
Na+ +
kidney(distal tubule)
AII-R+
MR
An increase in aldosterone ACTION can theoretically result from ANY defect in RAA pathway
-LOW IVV (real or perceived by kidney in renal artery stenosis)
Source Undetermined
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apparent mineralocorticoid excess (LOW ALDO/LOW RENIN) (downstream of ALDO) ! constitutively active MR <1% ! Na/K/H channel <1% ! licorice <1%
secondary hyperaldosteronism (HI ALDO/HI RENIN) ! JGA renin tumor <1% ! renal artery stenosis <1%
Primary Aldosteronism
primary hyperaldosteronism (HI ALDO/LOW RENIN) ! ZG Aldo tumor 70% ! ZG Aldo hyperplasia 30%
! rare/rare/rare ! Congenital adrenal hyperplasia <1%
(p450c11ß, p450c17) ! ACE polymorphisms < 1% ! AII overproduction < 1%
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Consider in patients with: -New HTN -HTN with LOW K EVEN THOUGH it only accounts for 0.5% of all HTN
BECAUSE- IF YOU NEVER THINK OF THIS-----YOU WILL NEVER FIND IT!!!
Primary Aldosteronism
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! IF NECESSARY (ie AMBIGUOUS) Volume expand to see if can suppress RAA ! If can suppress --essential HTN
! Work-Up ! R/O other causes of LOW K ! LOW intake (diet) ! HI output
! N/V/D ! Diuretic use with loops + thiazides
! 24 h Urine ALDO ! If LOW- pt does not have PRIMARY ALDO ! IF HI (>10 ug/day)
! check RENIN level (suppressed < 1 ng/ml/hr) ! If RENIN HI ----JGA renin tumor or RAS ! If RENIN LOW---- PRIMARY HYPERALDO
Primary Aldosteronism
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Adrenal Zona Glomerulosa Adenoma
Source Undetermined
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! IMAGING and TREATMENT ! CT scan ! Adenoma ! unilateral ADX
! NO adenoma ! selective venous cath to measure ALDO rt vs lt ! If unilateral elevation-small adenoma ! If no lateralization-bilateral hyperplasia
! Medical trt with spironolactone or amiloride ! bilateral ADX
Primary Aldosteronism
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Adrenocortical Carcinoma
! Larger adrenal mass
! High probability NOT benign if >5 cm in diameter
! ! Development of Cushingoid
features usually very rapid (several months rather than years)
! Often associated with elevated DHEA-sulfate and virulization
Source Undetermined
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Remember:!
Endocrine disorders are NOT diagnosed by means of imagining studies. Biochemical
confirmation must come first before imagining is performed.!
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“Even our destiny is determined by our endocrine glands.”
Albert Einstein
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Slide 5: Gray’s Anatomy, wikimedia commons, http://commons.wikimedia.org/wiki/File:Gray531.png; Wikimedia commons http://commons.wikimedia.org/wiki/File:Illu_adrenal_gland.jpg Slide 6: Sources Undetermined Slide 7: Gary Hammer Slide 8: Sources Undetermined Slide 11: Gary Hammer Slide 12: Regents of the University of Michigan Slide 13: Source Undetermined Slide 14: Source Undetermined Slide 15: Gary Hammer Slide 16: Source Undetermined Slide 17: SHBG Grishkovskaya et al, 1999 Slide 18: Source Undetermined Slide 20: Source Undetermined Slide 22: Arno Kumagai Slide 23: Arno Kumagai Slide 24: Arno Kumagai Slide 26: Source Undetermined Slide 30: Source Undetermined Slide 31: Alvesgaspar, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Wasp_August_2007-12.jpg, CC:BY-SA, http://creativecommons.org/licenses/by-sa/3.0/deed.en Slide 32: Arno Kumagai Slide 33: Source Undetermined Slide 34: Sources Undetermined Slide 35: Gary Hammer Slide 36: (Toilet) weegolo, flickr, http://www.flickr.com/photos/geoff_leeming/740423292/, CC:BY-NC, http://creativecommons.org/licenses/by-nc/2.0/deed.en; Source Undetermined Slide 37: Source Undetermined Slide 38: Source Undetermined Slide 39: Gary Hammer Slide 42: UK Medical Art Service, wellcome images, http://images.wellcome.ac.uk/, BY-NC-ND 2.0, http://creativecommons.org/licenses/by-nc-nd/2.0/uk/ Slide 43: Arno Kumagai Slide 44: UK Medical Art Service, wellcome images, http://images.wellcome.ac.uk/, BY-NC-ND 2.0, http://creativecommons.org/licenses/by-nc-nd/2.0/uk/ Slide 46: Arno Kumagai Slide 47: Gary Hammer Slide 48: Gary Hammer
Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy
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Slide 49: Gary Hammer Slide 50: Gary Hammer Slide 52: Source Undetermined Slide 59: N Engl J Med 1997;337:1666. Slide 60: Andreas Vesalius (1543) Book Five of De Corporis Humani Fabrica in 1543; Bartholomäus Eustachius (1564) glandulae quae renibus incumbent" in 1564 Slide 62: Gray’s Anatomy, wikimedia commons, http://commons.wikimedia.org/wiki/File:Gray531.png; Wikimedia commons http://commons.wikimedia.org/wiki/File:Illu_adrenal_gland.jpg Slide 63: Sources Undetermined Slide 64: Gary Hammer Slide 65: Gary Hammer Slide 66: inoc, flickr, http://www.flickr.com/photos/10918289@N07/2131039962/, CC:BY, http://creativecommons.org/licenses/by/2.0/deed.en Slide 67: Gary Hammer Slide 68: Source Undetermined Slide 70: Gary Hammer Slide 71: Gary Hammer; Slide 72: Sources Undetermined Slide 75: Source Undetermined Slide 77: N Engl J Med 1997;337:1666. Slide 78: Cecil Stoughton, White House; Cassandra Austen (c. 1810) Slide 81: Gary Hammer Slide 82: Gary Hammer Slide 83: Source Undetermined Slide 84: Gary Hammer Slide 85: Gary Hammer Slide 86: T. Addison “On the constitutional and local effects of disease of the suprarenal capsules” 1855; N Engl J Med 1997;337:1666.; Sources Undetermined Slide 87: Gary Hammer Slide 88: Gary Hammer Slide 89: Gary Hammer Slide 90: Gary Hammer Slide 96: Gary Hammer Slide 98: Gary Hammer Slide 99: Andreas Vesalius (1543) Book Five of De Corporis Humani Fabrica in 1543; Bartholomäus Eustachius (1564) glandulae quae renibus incumbent" in 1564; Source Undetermined Slide 104: Source Undetermined Slide 106: TRENDS in Endocrinology & Metabolism; Source Undetermined Slide 107: (Both images) TRENDS in Endocrinology & Metabolism Slide 112: Gary Hammer
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Slide 113: Sources Undetermined Slide 114: Sources Undetermined Slide 115: Sources Undetermined Slide 116: Source Undetermined Slide 117: Sources Undetermined Slide 120: Source Undetermined; Dr. Zak, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:HarveyCushing.JPG Slide 122: Source Undetermined Slide 124: Source Undetermined Slide 125: Gary Hammer; Dr. Zak, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:HarveyCushing.JPG Slide 126: Sources Undetermined Slide 127: Sources Undetermined Slide 128: Source Undetermined; Gary Hammer Slide 129: Sources Undetermined Slide 130: Gary Hammer Slide 132: Sources Undetermined Slide 133: Source Undetermined Slide 134: Sources Undetermined Slide 135: Sources Undetermined Slide 136: Source Undetermined Slide 138: Gary Hammer Slide 140: Gary Hammer Slide 141: Gary Hammer Slide 144: Sources Undetermined Slide 146: Sources Undetermined; Conn JW. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45:3-17 Slide 148: Source Undetermined Slide 152: Source Undetermined Slide 154: Source Undetermined
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