A condition that occurs from exposure to high cortisol levels for a long time. Fewer than 1 million cases per year (India) Treatable by a medical professional Requires a medical diagnosis Lab tests or imaging always required Chronic: can last for years or be lifelong The most common cause is the use of steroid drugs, but it can also occur from overproduction of cortisol by the adrenal glands. Signs are a fatty hump between the shoulders, a rounded face and pink or purple stretch marks. Treatment options include reducing steroid use, surgery, radiation and medication.

1. 
Adrenal Gland & Cushing's Syndrome
Presenter: Dr.Arun Vasireddy
Seminar – 10th August 2015

2. Overview
 History & Introduction
 Embryology & Anatomy
 Adrenal Cortex Physiology
 Cushing’s Syndrome – Etiology &
Classification
 Cushing’s Syndrome – Clinical Features
 Diagnosis & Management

3. History of Events
 1563 Eustachius describes the adrenals (published by Lancisi in 1714).
 1855 Thomas Addison describes the clinical features and autopsy findings in 11 cases of diseases of the
suprarenal capsules, at least 6 of which were tuberculous in origin.
 1856 In adrenalectomy experiments, Brown-Séquard demonstrates that the adrenal glands are essential for
life.
 1896 William Osler demonstrated clinical benefits in patients with Addison’s disease.
 1929 Liquid extracts of cortical tissue are used to keep adrenalectomized cats alive indefinitely (Swingle and
Pfiffner); subsequently, this extract was used successfully to treat a patient with Addison’s disease
 1932 Harvey Cushing associates the “polyglandular syndrome” of pituitary basophilism, which he first
described in 1912, with hyperactivity of the pituitary-adrenal glands.
 1950 Hench, Kendall, and Reichstein share Nobel Prize in Medicine for describing the anti-inflammatory
effects of cortisone in patients with rheumatoid arthritis.
 1980-present The “molecular era”: cloning and functional characterization of steroid receptors, steroidogenic
enzymes, and adrenal transcription factors are reported, and the molecular basis for human adrenal diseases
is defined.

4. Embryology

5. Anatomy
 There are 2 adrenal glands each weighing about 4
gms
 They lie at the superior poles of the two kidneys
 Each gland is composed of two distinct parts
adrenal cortex and adrenal medulla
 Blood supplied by superior ,inferior and middle
adrenal arteries

7. Adrenal cortex
Three distinct layers-
 Zona glomerulosa- thin layer under the capsule 15% of
the cortex. The cells here capable of secreting significant
amount of aldosterone
 Zona fasiculata- middle widest layer 75%of cortex
secreting glucocorticoids, cortisol and corticosterone as
well as small amount of adrenal androgens and estrogen
 Zona reticularis- deep layer secretes adrenal androgens
dehydroepiandrosterone(DHEA) and androstenedione as
well as small amount of estrogen and glucocorticoid

8. Adrenal medulla
 It occupies the central 20 % of the adrenal gland
 It secretes the hormones epinephrine and nor
epinephrine in response to sympathetic stimulation
they are referred to as catecholamines

9. Biosynthesis of adrenal steroids
 Important steroid products of adrenal cortex are aldosterone , cortisol and
androgens
 All the steps of synthesis occurs in mitochondria and endoplasmic
reticulum
 Approx 90-95% of cortisol in plasma binds to plasma protein globulin
called transcortin and to albumin
 Binding serves as a reservoir to lessen rapid fluctuations in free hormone
concentration
 Adrenal steroids are degraded mainly by liver and conjugated to
glucoronic acid or sulphates
 25% of these conjugates are excreted in the bile and then in feces and
remaining in urine

11.  The adrenal cortex produces three major classes of steroids:
• Glucocorticoids,
• mineralocorticoids, and
• adrenal androgens.
Consequently, normal adrenal function is important for
-modulating intermediary metabolism and immune responses through
glucocorticoids;
- blood pressure, vascular volume, and electrolytes through
mineralocorticoids;
- secondary sexual characteristics (in females) through androgens.
- The adrenal axis plays an important role in the stress response by rapidly
increasing cortisol levels.
- Adrenal disorders include hyperfunction (Cushing's syndrome) and
hypofunction (adrenal insufficiency) as well as a variety of genetic
abnormalities of steroidogenesis.

12. Glucocorticoids
 95% of glucocorticoid activity occurs from secretion
of cortisol known as hydrocortisone
 Cortisol has effects on
 Carbohydrate metabolism
 Protein metabolism
 Fat metabolism
 Antiinfammatory effects

14. Regulation of cortisol secretion
• Hypothalamic-pituitary-adrenal axis.
• Adrenocorticotropic hormone (ACTh) is
secreted from the anterior pituitary
under the influence of two principal
secretagogues, corticotropin-releasing
hormone (Crh) and arginine vasopressin;
other factors, including cytokines, also
play a role.
• Crh secretion is regulated by an inbuilt
circadian rhythm and by additional
stressors operating through the
hypothalamus.
• Secretion of Crh and ACTh is inhibited by
cortisol, highlighting the importance of
negative feedback control.

16. Principal pathways of cortisol metabolism
• The Interconversion of hormonally
active cortisol to inactive cortisone is
catalyzed by two isozymes of 11β-
hydroxysteroid dehydrogenase (11β-
hSd), with hSd11B1 principally
converting cortisone to cortisol and
hSd11B2 doing the reverse.
• Cortisol can be hydroxylated at the C6
and C20 positions.
• A ring reduction is undertaken by 5α-
reductase or 5β-reductase and 3α-
hSd.

17. Regulation of cortisol secretion
 ACTH stimulates cortisol secretion
 Secretion of cortisol is controlled
entirely by ACTH
 ACTH activates by increase in
cAMP
 ACTH acts on adrenaocortical
cells to activate adeny cyclase
 Long term activation can cause
hypertrophy
 Inhibitory effect of cortisol
 Cortisol sends negative feedback
to hypothalamus and pituitary to
regulate cortisol levels

18. B. General effects:
1.On C.V.S.
a) Cortisol increases blood pressure
because of increased production of
angiotensionogen.
b) Increased sensibility of vascular smooth
muscle to nor-adrenaline and
adrenaline.

19. 2. On blood cells:
a) Increases the platelet count.
b) Decreases blood clotting time.
c) Increases total WBCs.
d) Decreases lymphocytes, eosinophils and basophils.
e) Increases neutrophils, monocytes and RBC count.

20. 3. On C.N.S. :
a) Low cortisol levels cause restlessness, insomnia, and inability
to concentrate.
b) Causes excitation of the CNS.
4. On GIT:
a) Increases gastric acidity and may cause a peptic ulcer.

21. 5. On bone:
a) Excess cortisol may cause a defect in the
synthesis of protein matrix.
b) It decreases the deposition of calcium.
c) It increases the loss of calcium in urine.
d) It decreases absorption of calcium from the
GIT.

22. 6. On infection, inflammation, and trauma:
a) Large doses of cortisol decrease the formation of antibodies
due to its destructive effect on lymphoid tissues.
b) It decreases tissue response to bacteria.
c) It is anti- inflammatory.
d) It is anti- allergic.
e) It delays wound healing.

23. Effect of cortisol in preventing
inflammation
 Cortisol stabilizes the lysosomal membrane
 Cortisol decreases the permeability of the capillaries
preventing loss of plasma into tissues
 Cortisol decreases migration of WBCs into inflamed area
and phagocytosis of damaged cells
 Cortisol suppresses the immune system causing
lymphocyte reproduction to decrease
 Cortisol attenuates fever as it reduces the release of
interleukin-1

24. COMMONTHERAPUTIC USES OF
GLUCOCORTICOIDS
 Bronchial asthma.
 Chronic bronchitis.
 Emphysema.
 Sarcoidosis.
 Ulcerative colitis.
 Crohn’s disease.
 SLE, cerebral edema.
 Skin diseases.
 Hodgkin’s disease.

25. SUMMARY OF ADVERSE EFFECTS OF
GLUCOCORTCOIDS
 Hypertension.
 Peptic ulcer, pancreatitis.
 Nocturia, polyurea.
 Insomnia, depression and psychosis.
 Amenorrhea.
 Hyperglycemia.
 Osteoporosis.
 Pathological fractures.
 Cataract.

26. Etiology & Classification

27.  A constellation of clinical abnormalities due to
chronic exposure to inappropriately elevated levels
of free plasma glucocorticoids.
 described by Harvey Cushing in 1932
Cushing’s Syndrome

29. COMMON CAUSES OF ECTOPIC ACTH SECRETION
Small cell carcinoma of the lung 50%
Endocrine tumors of foregut origin 35%
Thymic carcinoid
Islet cell tumor
Medullary carcinoma thyroid
Bronchial carcinoid
Pheochromocytoma 5%
Ovarian tumors 2%

30. Hyperadrenalism- Cushing’s syndrome
Hypercorticolism can occur due to-
 Adenomas of the anterior pitutary secreting increased ACTH
 Abnormal function of hypothalamus causing increased CRH
and thereby increased ACTH
 Ectopic secretion of ACTH by a tumor somewhere else in the
body
 Adenomas of the adrenal cortex
When cushing’s syndrome is secondary to excess secretion of
ACTH by the anterior pituitary this is called Cushing’s disease

31. Clinical features

33. Clinical Features
Hypercotisolism
Lipid mobilization 
Lipid catabolism 
Lipid redistribution
Moon-face
buffalo hump
truncal obesity
Violaceous striae
Hepatic glucose
production
Insulin resistance
Glucose intolerance
• protein metabolism
• negative nitrogen balance
• disruption of water and electrocytes
metabolism
Proximal muscle
weakness
Dependent edema
Hypertension
Hypokalemic metabolic alkalosis

34. Cushing’s Disease

35. Ectopic ACTH Syndrome
 In 15% of cases, Cushing’s syndrome is associated with nonpituitary
tumors secreting ACTH—the ectopic ACTH syndrome
 Circulating ACTH concentrations and cortisol secretion rates can be
extremely high.
 As a result, duration of symptoms from onset to presentation is short
(<3 months); patients are commonly pigmented, and the metabolic
manifestations of glucocorticoid excess are often rapid and
progressive.
 Weight loss, myopathy, and glucose intolerance are prominent
symptoms and signs.
 The association of these features with hypokalemic alkalosis and
peripheral edema should alert the clinician to the diagnosis.

36. Ectopic Corticotropin-Releasing
Hormone Syndrome
 Ectopic production of CRH is a very rare cause of pituitary-
dependent Cushing’s.
 Pituitary histology has revealed corticotroph hyperplasia but
not adenoma formation.
 Biochemically, these patients, like those with ectopic ACTH
syndrome, lose the normal negative glucocorticoid feedback
mechanism—50% have resistance to high-dose dexamethasone
therapy.
 Ectopic CRH production may explain the suppression of cortisol
secretion after high- dose dexamethasone that is observed in
some patients with the “ectopic” ACTH syndrome.

37. Macronodular Adrenal Hyperplasia
 In 10% to 40% of patients with Cushing’s disease, there is bilateral
adrenocortical hyperplasia associated with one or more nodules,
which may be up to several centimeters in diameter.
 Pathologically, the nodules are lobulated and can be markedly
enlarged, but internodular hyperplasia is invariably found.
 Macronodular adrenal hyperplasia (MAH) is thought to result from
long-standing adrenal ACTH stimulation, which leads to autonomous
adrenal adenoma formation.
 Therefore, as the adrenals in a patient with Cushing’s disease become
more hyperplastic, they secrete more cortisol for a given ACTH level,
which ultimately can lead to autosuppression.
 The adenomas can be a trap for the unwary because they may be
mistaken for primary adrenal tumors.

38. Cortisol-Secreting Adrenal Adenoma
and Carcinoma
 Excluding iatrogenic cases, adrenal adenomas are responsible for about 10%
to 15% of Cushing’s syndrome cases, and carcinomas for less than 5%.
 Onset of clinical features is gradual in patients with adenomas, but it is often
rapid in adrenal carcinoma. In addition to the features of hypercortisolism,
patients may complain of loin or abdominal pain, and a tumor may be
palpable.
 The tumor may secrete other steroids, such as androgens or mineralo-
corticoids.
 Therefore, in females, there may be features of virilization, with hirsutism,
clitoromegaly, breast atrophy, deepening of the voice, temporal recession,
and severe acne.
 Subclinical Cushing’s syndrome has been reported in up to 10% of patients
with adrenal “incidentalomas”

39. Primary Pigmented Nodular Adrenal
Hyperplasia and Carney’s Syndrome
 About 100 cases of ACTH-independent Cushing’s syndrome
have been reported in association with bilateral, small,
pigmented adrenal nodules.
 Pathologically, these nodules are usually 2 to 4 mm in diameter
(although they can be larger) and black or brown on cut section.
 Adjacent adrenal tissue is atrophic, distinguishing this primary
pig- mented nodular adrenal hyperplasia (PPNAD) from MAH.
Presentation is with typical features of Cushing’s syndrome in
persons younger than 30 years of age .
 Bilateral adrenalectomy is curative.

40. Carney’s complex
 A familial autosomal dominant variant.
 Mutations of the gene encoding the protein kinase
A (PKA) regulatory subunit type IA (PRKAR1A)
 comprises mesenchymal tumors (especially atrial
myxomas), spotty skin pigmentation, peripheral
nerve tumors, and various other tumors including
breast lesions, testicular tumors, and GH-secreting
pituitary tumors.

41. McCune-Albright Syndrome
 Here, fibrous dysplasia and cutaneous pigmentation may be
associated with pituitary, thyroid, adrenal, and gonadal
hyperfunction.
 The most common manifestation is with sexual precocity and GH
excess, but Cushing’s syndrome has been reported.
 The underlying abnormality is a somatic mutation in the α-subunit of
the stimulatory G protein, which is linked to adenyl cyclase.
 The mutation results in constitutive activation of the G protein,
mimicking constant ACTH stimulation at the level of the adrenal.
 ACTH levels are suppressed, and adrenal adenomas may occur.

42. Iatrogenic Cushing’s Syndrome
 Development of the features of Cushing’s syndrome depends on the dose,
duration, and potency of the corti- costeroids used in clinical practice.
 ACTH is rarely prescribed, but it will also result in cushingoid features if
administered long-term.
 Some features, such as an increase in intraocular pressure, cataracts, benign
intracranial hypertension, aseptic necrosis of the femoral head,
osteoporosis, and pancreatitis, are more common in iatrogenic than
endogenous Cushing’s syndrome,
 other features, notably hypertension, hirsutism, and oligomenorrhea/
amenorrhea, are less prevalent.

43. Cyclic Cushing’s Syndrome
 Characterized by periods of excess cortisol production interspersed with
intervals of normal cortisol production
 Some of these patients demonstrate a paradoxical rise in plasma ACTH and
cortisol when treated with dexamethasone, and occasionally a patient is
benefited by dopamine agonist (bromocriptine) or serotonin antagonist
(cyproheptadine) therapy.
 Most patients have been thought to have pituitary- dependent disease, and
in many of these patients, basophil adenomas have been removed, with
long-term cure in some cases.
 However, cortisol secretion may show some evidence of cyclicity in patients
with an ectopic source of ACTH.

44. Pseudo-Cushing’s Syndromes
 defined as the presence of some or all of the clinical features
of Cushing’s syndrome together with some evidence for
hypercortisolism.
 Resolution of the underlying cause results in disappearance of
the cushingoid state.
 Causes: Alcoholism, Depression & Obesity.

45.  Clinical manifestations
 Cortisol levels in blood are normally elevated at 8 A.M. and
decrease to less than 50% by midnight except in infants and
young children in whom a diurnal rhythm is not always
established.
 In patients with Cushing syndrome this circadian rhythm is lost,
and cortisol levels at midnight and 8 A.M. are usually
comparable.
 Urinary excretion of free cortisol is increased. This is best
measured in a 24-hr urine sample and is expressed as a ratio of
micrograms of cortisol excreted per gram of creatinine.
Diagnosis

48.  Dexamethasone is an exogenous steroid that provides negative
feedback to the pituitary to suppress the secretion of ACTH.
 This steroid is unable to pass the blood brain barrier which allows this
test to assess a specific part of the hypothalamic-pituitary-adrenal axis.
Specifically, dexamethasone binds to glucocorticoid receptors in the
pituitary gland, which lies outside the blood brain barrier, resulting in
regulatory modulation
 A single-dose dexamethasone suppression test is often helpful; a dose
of 25–30 μg/kg (maximum of 2 mg) given at 11 P.M. results in a plasma
cortisol level of less than 5 μg/dL at 8 A.M. the next morning in normal
individuals but not in patients with Cushing syndrome.
 A low dose dexamethasone suppresses cortisol in individuals with no
pathology in endogenous cortisol production. A high dose
dexamethasone exerts negative feedback on pituitary ACTH producing
cells but not on ectopic ACTH producing cells or adrenal adenoma.
Dexamethasone suppression test

49. Low-dose DX suppression test
 A normal result is decrease in cortisol levels upon
administration of low-dose dexamethasone.
 Cushing's disease involve no change in cortisol on low-dose
dexamethasone, but inhibition of cortisol on high-dose
dexamethasone

50.  Large dose DX suppression test
 D.X 2mg q6h P.O 2 days
 Urinary free cortisol reduced 50%: Cushing’s disease (Pituitary
adenoma)
 Urinary free cortisol NOT reduced 50%:Adrenal tumor, carcinoma,
ectopic ACTH Syndrome

51.  ACTH 25u intravenously 8h
 2-5 fold increase in urinary free cortisol in Cushing’
s disease
 Plasma cortisol and urinary free cortisol increase in
half of adrenal adenoma patients
 No response in adrenal carcinoma
ACTH Stimulation test

53.  Etiology diagnose (especially for pituitary ACTH-dependent
or ectopic ACTH syndrome)
 A newer approach is to combine a CRH stimulation test with
a dexamethasone suppression test(4mg ).
 Method :
1 µg / kg of CRH is administered intravenously.
ACTH and cortisol levels are measured before CRH injection
and 15, 30, 45, 60, 90 and 120 minutes after injection.
 A rise in the cortisol value of 20 percent or more above
basal level or a rise in the ACTH value of at least 50 percent
above basal level is considered evidence for an ACTH-
dependent lesion
CRH stimulation test

54.  Etiology diagnose (especially for pituitary or adrenal)
 Metyrapone (30mg/kg) P.O at midnight
 Urinary 17-OHCS, Plasma ACTH,11-deoxycortisol more above
basal level : Cushing’s disease (Pituitary adenoma)
 No response in adrenal carcinoma , tumor, ectopic ACTH
Syndrome
Metyrapone Test

55.  Pituitary CT has a sensitivity of about 50% for identifying
microadenomas
 MRI has increased sensitivity but is not 100% predictive
 If diagnostic doubt need bilateral inferior petrosal sinus
sampling for ACTH
 Adrenal ultrasonography---first choice
 Abdominal CT will allow identification of adrenal pathology
 Somatostatin scintigraphy to identify sites of ectopic hormone
production
Imaging diagnosis

59.  Cushing’ s disease:
 Adrenal adenoma:
 Adrenal carcinoma:
 Ectopic ACTH Syndrome:
 Chronic, moderate clinical features can be
suppressed by large dose test
 Shorter course , mild features can NOT be
suppressed by large dose test
 Acute onset, progressive course,
hyperandrogenic effect predominate,
palpable mass, low ACTH
 Appear suddenly, progress rapidly, not typical
manifestation of Cushing’s syndrome,
hyperpigmentation, hypokalemia, high ACTH
Etiological diagnosis

60.  Cushing’s disease
 Transsphenoidal microadenomectomy
 Pituitary radiation
 Bilateral total adrenolectomy
 Drugs
 Adrenal adenoma and carcinoma
 Surgical removal
 Drugs ( mitotane, metyrapone, ketoconazole ) for nonresectable or
metastatic carcinoma
 Ectopic ACTH Syndrome
 Surgical removal of the ectopic tumor
 Chemotherapy, radiotherapy
 Drugs ( mitotane, metyrapone, ketoconazloe )
Treatment

61.  Purpose
 Correct metabolic abnormalities before
attempted surgical cure
 Palliate surgically noncurable disease
 Achieve remission in patients for whom
surgery is unlikely to achieve satisfactory
long term results
Medical therapy of Cushing’ s Disease

62.  Steroidogenic inhibition
 Mitotane
 Metyrapone
 Aminoglutethimide
 Ketoconazole
 Neuromodulatory treatment
 Bromocriptine
 Cyproheptadin
 Valproic acid
 Octreotide
 Glucocorticoid receptor antagonist
 RU486

63. Glucocorticoid Resistance
 A small number of patients have been described as having increased
cortisol secretion but without the stigmata of Cushing’s syndrome.
 These patients are resistant to suppression of cortisol with low-dose
dexamethasone but respond to high doses.
 ACTH levels are elevated and lead to increased adrenal production of
androgens and DOC. Therefore, these patients may present with the
features of androgen or mineralocorticoid excess, or both.
 Treatment with a dose of dexamethasone (usually >3 mg/day)
adequate to suppress ACTH results in a fall in adrenal androgens and
often returns plasma potassium and blood pressure to normal levels.
 Many of these patients have been found to have point mutations in
the steroid-binding domain of the GR, with consequent reduction of
glucocorticoid-binding affinity, but this is not invariable.

64. Prognosis of Cushing’s Syndrome
 Studies carried out before the introduction of effective therapy
revealed that 50% of patients with untreated Cushing’s
syndrome died within 5 years, principally from vascular disease.
 Even with modern management, an increased prevalence of
cardiovascular risk factors persists for many years after an
apparent “cure.”
 Paradoxically, on correction of the hypercortisolism, patients
often feel worse.
 Skin desquamation, steroid-withdrawal arthropathy, profound
lethargy, and mood changes may occur and can take several
weeks or months to resolve

65. o Features of Cushing’s syndrome disappear over a period of 2 to
12 months after treatment.
o Hypertension and diabetes mellitus improve, but, as with other
secondary causes, they may not resolve completely.
o The osteopenia of Cushing’s syndrome improves rapidly during
the first 2 years after treatment but resolves more slowly
thereafter.
o Vertebral fractures and osteonecrosis are irreversible, and
permanent deformity results. Visceral obesity and myopathy are
both reversible features.
o Reproductive and sexual func- tion return to normal within 6
months, provided that anterior pituitary function was not
compromised.

66. 
ThankYou
References:
 Harrison’s principles of Internal Medicine 19th Ed.
 WilliamsTextbook of Endocrinology 12th Ed.
 Ferri's ClinicalAdvisor 2015
 Online Source – Pubmed Central