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The Adrenals. דר. אביטל נחמיאס. The Adrenals. Structure and function Cortex Hypofunction – Addison Hyperfunction – Cushing Adrenal incidentaloma. The Adrenal Glands. בלוטת יותרת הכליה היא איבר רטרופריטוניאלי שנראה כמו כובע משולש מעל כל כליה

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The Adrenals

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the adrenals

The Adrenals

דר. אביטל נחמיאס

the adrenals1
The Adrenals
  • Structure and function
  • Cortex
    • Hypofunction – Addison
    • Hyperfunction – Cushing
  • Adrenal incidentaloma
the adrenal glands
The Adrenal Glands

בלוטת יותרת הכליה היא איבר רטרופריטוניאלי שנראה כמו כובע משולש מעל כל כליה

המשקל של כל בלוטה הוא כ-4 גרם והמידות הן 2-3 X 4-6 cm


The Adrenal Glands


4 gr weight

2X4X1 cm


Morphology of the Adrenal









adrenal cortex
Adrenal Cortex

Zona glomerulosa- 15%

Mineralocorticoid - Aldosterone

Zona fasciculata- 75%

Glucocorticoid - Cortisol and DHEA

Zona reticularis- 10%

Androgens - DHEA (DeHydroEpiAndrosterone), DHEAS

DHEAS הוא ההורמון הפעיל שאחראי על כל סימני הויריליזציה

actions of glucocorticoids
Actions of glucocorticoids
  • Immune system
    • ↑ WBC, ↓Eos, ↓ phagocytosis, anti inflammatory
  • Metabolic
    • Increase gluconeogenesis
    • Inhibit glucose uptake and utilization (NOT in brain, heart, liver, RBC)
    • Increase lipolysis, increase protein catabolism - myopathy
    • Impaired wound healing (less colagen production, impaired fibroblast function)
    • Inhibit osteoblasts (osteoporosis), ↓ intestinal and renal calcium absorption – increases PTH
  • Developmental
    • Differentiation of organs in the fetus
  • Complex action on the brain - arousal and cognition
action of mineralocorticoids
Action of mineralocorticoids
  • Increased Na absorption in the kidney – water comes with the Na – fluid overload – hypertention and edema
  • K+ secreted instead of the Na – hypokalemia
regulation of androgen secretion
Regulation of androgen secretion
  • Adrenal androgen secretion is regulated by ACTH
  • In males – adrenal androgens have minimal effects
  • In females – adrenal androgens convert to testosterone in extraglandular tissues
laboratory evaluation of adrenal function1
Laboratory evaluation of adrenal function
  • Point measurements – at peak or trough
  • Urinary excretion
  • Dynamic testing
    • Stimulation – for suspected deficiency
    • Suppression – for suspected excess
s timulation tests
Stimulation tests
  • Cortisol
    • ACTH (synacthen test)
  • Aldosterone
    • Volume depletion
      • Salt restriction
      • Diuretic administration
      • Upright posture
suppression test
Suppression test
  • Cortisol
    • Dexamethasone suppression test
  • Aldosterone
    • Saline infusion test
adrenal failure
Adrenal Failure
  • Primary (Addison’s Disease)

Adrenal dysfunction

Both GC and MC deficiency; ACTH.

  • Secondary

Pituitary Dysfunction

Only GC deficiency;ACTH.


“general languor and debility, feebleness of the heart's action, irritability of the stomach, and a peculiar change ofthe color of the skin"

Thomas Addison

The first description of Addison’s disease

etiology of addison s disease
Etiology of Addison’s Disease

Autoimmune (80%)

Isolated, Autoimmune polyglandular syndrome Type 1&2


TB (calcifications), Histoplasmosis, CMV, HIV, syphillis, coccidioidomycosis, and cryptococcosis.


Amyloidosis, Hemochromatosis


Anticoagulants, trauma, sepsis, surgery, pregnancy, Meningococcemia causes waterhouse friderichsen syndrome – adrenal crisis)

Infarction (bilateral – rare)

etiology of addison s disease1
Etiology of Addison’s Disease
  • Bilateral Metastasis, Lymphoma (rare)
  • Bilateral adrenalectomy
  • Drugs
  • Inhibitors of steroidogenesis (ketoconazol)
  • Increase metabolism of steroid hormones (tegretol)
  • Congenital Adrenal Hyperplasia
  • Familial GC deficiency
secondary hypoadrenalism acth
Secondary Hypoadrenalism (ACTH)
  • Iatrogenic
  • Abrupt withdrawal of Chronic steroid Rx
  • Pituitary
  • Tumor (stalk effect)
  • Radiation
  • Surgery
  • Infarct
  • Hemorrhage
  • Sheehan syn – low BP during birth +/- hemorrhage
autoimmune addison s disease
Autoimmune Addison’s Disease
  • Autoimmune Polyglandular Syndrome Type 1
  • AR inheritance
  • More common in Iranian Jews
  • Hypoparathyroidism
  • Chronic Mucocutaneous Candidiasis
  • Gonadal failure
  • Addison
  • Ab in serum can be sent abroad
autoimmune addison s disease1
Autoimmune Addison’s Disease
  • Autoimmune Polyglandular Syndrome Type 2
  • 50:1,000,000 rare
  • More common in women, age 30-50
  • DM type 1
  • Vitiligo
  • Graves or hashimoto
  • Addison
  • Pernicious anemia
clinical features of adrenal insufficiency
Clinical Features of Adrenal Insufficiency

Chronic syndrome

Symptoms (not specific):

Weakness & fatigue 100%

Anorexia 100%

Gastrointestinal symptoms 92%


Weight loss 100%Hyperpigmentation (primary) 92%

Hypotension 88%

Salt craving (primary) 19%

Postural hypotension symptoms 12%




ל ACTH ברמות גבוהות יש פעילות של MSH הורמון המפעיל מלנוציטים

laboratory findings
Laboratory Findings
  • Normocytic normochromic anemia (chronic disease)
  • Neutropenia and eosinophilia, relative lymphocytosis
  • Hyponatremia (SIADH, MC def) (90%)
  • Hyperkalemia (65%)
  • Hypoglycemia (rare)
  • Hypercalcemia (rare)
  • Primary adrenal insufficiency:
  • Rapid ACTH test (Synacthen 250 mg)
  • Post-stimulation cortisol (30’ 60’) above 550 nmol/l (20 mg/dl) is normal, Below 200 could be addison
  • Plasma ACTH levels
  • Secondary/ tertiary adrenal insufficiency:
  • CRH test
acute syndrome addisonian crisis
Acute Syndrome (Addisonian Crisis)
  • Withdrawal
  • Acute stress
        • Infection
        • trauma
        • Surgery
        • Dehydration
  • Acute syndrome
      • Hemorrhage
      • Infarct
      • Meningococcemia (Waterhouse-Friderichsen syndrome)
  • Rare in secondary adrenal insufficiency.
acute syndrome addisonian crisis1
Acute Syndrome (Addisonian Crisis)
  • Manifestations:
      • Shock and hypotension
      • Weakness, fatigue, lethargy
      • Muscle, joint and abdominal pain (acute abdomen)
      • Fever, anorexia, vomiting
      • Apathy, Clouded sensorium
      • Hypoglycemia is rare
  • The diagnosis should always be considered in any patient with unexplained shock

This is a life threatening emergency!!!

  • Acute Crisis
  • Hydrocortisone 100 mg IV, every 6-8 hours for 24 hr not PO !!!
  • Correct volume depletion, dehydration, hypotension
  • and hypoglycemia with IV saline and glucose
  • Correct precipitating factors, especially infection
  • As soon as the patient is eating and drinking and off IV fluids add fludrocortisone.
  • Hydrocortisone 15-20 mg in the morning & 5-10 mg at 4-6 PM or prednisone 5-7.5 mg orally once a day
  • Fludrocortisone 0.05-2 mg/day (primary)
  • Follow clinical symptoms, weight, B.P., electrolytes
  • Educate patient to increase cortisol dose during stress
cushing s disease

Cushing’s disease

Harvey Williams Cushing

etiology of cushing s syndrome cs
Etiology of Cushing’s syndrome (CS)

Exogenous: (Iatrogenic, Factitious)


ACTH dependent: Pituitary (68%)

Ectopic ACTH (SCLC)(15%)

CRH rare

ACTH independent: Adenoma (9%)

Carcinoma (8%)

Nodular hyperplasia rare

Cushing’s disease

cushing s syndrome symptoms
Cushing’s Syndrome- Symptoms

Feature %

Weight gain 91

Hirsutism, acne 82

Menstrual disturbances/Dec. libido 76

Psychiatric dysfunction 60

Back pain 43

Muscular weakness 29

Fractures (osteoporosis)

 Infections

cushing s syndrome signs
Cushing’s Syndrome- Signs

Feature %

Central obesity (viceral fat) 97

Plethora 94

Moon face 88

HTN 74

Easy bruising (colagen fibroblasts) 62

Red striae 56

Muscle weakness 56

Edema 50

cushing s syndrome lab
Cushing’s Syndrome- Lab
  • DM +IGT
  • Osteoporosis (hypercalciuria, inc. PTH)
  • Hypercalciuira
  •  LH& FSH
  • TSH
  • GH
  • TC; TG
  • K
diagnosis of cushing s syndrome
Diagnosis of Cushing’s Syndrome
  • Does the patient have Cushing’s syndrome?
  • If the answer is yes: What is the cause of the hypercortisolism?

ACTH dependent

ACTH independent

does the patient have cushing s syndrome
Does the patient have Cushing’s syndrome?

Loss of circadian rhythm of plasma cortisol and ACTH.

  • Peak 8-9 AM; Nadir 24:00
  • Midnight cortisol

>200 nmol/l suggestsCushing’s; <50nmol/l R/O Cushing’s

24 Hour Urinary Free Cortisol (UFCX3)

Inexpensive, outpatient

 suspicion if X3-4 ULN

1mg Overnight Dexamethasone suppression test (ONDST)

1 mg dexamethasone PO @ midnight

8 AM cortisol <50 nmol/l

Does the patient have Cushing’s syndrome?

does the patient have cushing s syndrome1
Does the patient have Cushing’s syndrome?

Low dose dexamethasone tests

  • 0.5mg X4 for 2 days (2mg/d).
  • 8 AM cortisol on day 3 <50 nmol/l
pituitary cushing s vs ectopic acth the high dose dexamethasone test
Pituitary Cushing’s vs. Ectopic ACTHThe High Dose Dexamethasone Test
  • ACTH secretion by pituitary adenomas is only relatively resistant to negative feedback regulation by GC’s.
  • Most tumors associated with the ectopic ACTH syndrome are completely resistant to feedback inhibition
high dose dexamethasone suppression test liddle s test
High Dose Dexamethasone Suppression Test- Liddle’s test
  • One baseline 24-hour urine specimen
  • 2 mg of dexa X4 (8mg/d) for 2 days.
  • Suppression of urinary cortisol excretion by more than 90%→100% specific for Cushing's disease
pituitary cushing s vs ectopic acth inferior petrosal sinus sampling
Pituitary Cushing’s vs. Ectopic ACTH- Inferior Petrosal Sinus Sampling
  • Some pituitary Cushing’s don’t suppress with HDDST
  • Some ectopic ACTH syndrome suppress with HDDST
  • MRI sensitivity in pituitary imaging is only 50%-60%
  • 10-20% incidental pituitary tumors in the general population

Measure cortisol and ACTH simultaneously from:

  • Right petrosal sinus
  • Left petrosal sinus
  • Peripheral vein

Before and after stimulation with CRH (100 ucg).

Central/Peripheral >3 → Pituitary Cushing’s

Central/Peripheral <2 → Ectopic ACTH

treatment of cushing s syndrome
Treatment of Cushing’s syndrome

Pituitary CS:

Trans-sphenoidal adenomectomy (80-90% cure)

Irradiation (conventional, proton beam)

Medical treatment

Bilateral adrenalectomy

Ectopic ACTH

Tumor resection (if possible)

Medical treatment

Bilateral adrenalectomy

Adrenal CS

Tumor resection

medical treatment of cs
Medical Treatment of CS

Drug Mechanism

Metyrapone CYP11B1 inhibitors

Ketoconazole CYP11A1+B1inhibitors

evaluation of asymptomatic adrenal masses
Evaluation of Asymptomatic Adrenal Masses
  • ~6% of adult/elderly subjects at autopsy have adrenocortical adenomas.
  • Determine whether the patient has a history of prior malignancy.
      • metastasis in about one-half of the patients.
  • Determine whether the tumor is functioning
      • 70–80% are non-secretory.
  • CT Features suggestive of malignancy include
      • large size (>4–6 cm)
      • irregular margins
      • tumor inhomogeneity
      • soft tissue calcifications visible on CT
      • high unenhanced CT attenuation values (>10 HU)