Cushing's syndrome results from prolonged exposure to excess glucocorticoids and is associated with poor suppressibility of cortisol production with dexamethasone. The most common cause is exogenous glucocorticoid administration, while endogenous causes include pituitary adenomas (70%), adrenal adenomas or carcinomas (15%), and ectopic ACTH secretion (10%). Diagnosis involves tests like the overnight low-dose dexamethasone suppression test and 24-hour urine free cortisol. Treatment depends on the underlying cause, and may include transphenoidal pituitary surgery, adrenalectomy, pituitary irradiation, or medical therapy with cortisol synthesis inhibitors.

1. DR. IGBITI O.J.
REGISTRAR, INTERNAL MEDICINE DEPARTMENT
CUSHING’S
SYNDROME

2. Outline
o Introduction
o Epidemiology
o Relevant anatomy and physiology
o Aetiology
o Clinical features
o Diagnostic approach
o Treatment
o Summary/key points
o Conclusion
o References

3. Introduction
Cushings syndrome is a constellation of clinical
features resulting from prolonged exposure to excess
glucocorticoids of any aetiology.

4. Epidemiology
o The exact incidence of Cushing syndrome is challenging.
o The true incidence might be underestimated.
o Globally, it is considered a rare disease with an incidence of 1-2 per
100,000 population per year.
o In a European population based study, the annual incidence of
endogenous cushing’s syndrome was reported to be 1.2-1.7 per
million per year.
o LUTH: It has an incidence of 2-5 new cases /million people/year
and 10% of these new cases occur in children

5. Epidemiology
o The female-to-male incidence ratio is approximately 5:1
for Cushing syndrome due to an adrenal or pituitary tumor.
o Ectopic ACTH production is more frequent in men than in
women.
o The peak incidence of Cushing syndrome due to either an
adrenal or pituitary adenoma is in persons aged 25-40
years.

6. Functional anatomy
o 2 adrenal glands sit on top of the
kidneys
o The Cortex forms about 90% of
the adrenal mass
o Medulla 10%
o Synthesizes and secretes steroid
hormones from cholesterol
o Blood supply from the branches
of the aorta, phrenic and renal
arteries

7. Steroid synthesis

8. Steroid synthesis

9. Regulation of cortisol synthesis

10. Regulation of cortisol synthesis

11. Etiology
o ACTH-dependent
o (Pseudo Cushing’s Syndrome)
o Pituitary (Cushing’s Disease) (70%)
oMicroadenomas (95%)
oMacroadenomas (5%)
o Ectopic ACTH or CRH (10%)
oSmall cell lung carcinoma
oCarcinoids: lung, pancreas, thymus

12. Etiology
o ACTH-independent
o (Factitious)
o Unilateral
oAdrenal adenoma (10%)
oAdrenal carcinoma (5%)
o Bilateral
oMacronodular Hyperplasia (AIMAH) (<2%)
oPrimary Pigmented Micronodular Adrenal disease - PPMA (<2%)
oMcCune Albright Syndrome (<2%)

13. Clinical features
o General
o Truncal obesity
o Proximal muscle
weakness
o Hypertension
o Headaches

14. Clinical features
o Dermatologic
o Wide purple striae
o Spontaneous ecchymoses
o Facial plethora
o Hyperpigmentation
o Acne, hirsutism
o Fungal skin infections

15. Clinical features

16. Clinical features
o Endocrine/Metabolic
o Hypokalemic alkalosis
o Hypokalemia
o Osteopenia
o Hypogonadism
o Glucose intolerance
o Hyperlipidemia
o Hyperhomocysteinemia
o Kidney stones
o Polyuria
o Hypercoagulability

17. Clinical features
o Neuropsychiatric
o Insomnia
o Depression, frank psychosis
o Impaired cognition and short-term memory

18. Making a diagnosis
1. Establishing the diagnosis of Cushing’s Syndrome
2. Establishing the cause of Cushing’s Syndrome
a. ACTH-dependent vs independent
b. Identifying the source in the ACTH-dependent forms
3. Imaging

19. Physiological principles
o Cortisol hypersecretion in most patients with Cushing’s
Syndrome is cyclical
o There is loss of circadian rhythm in pts with CS
o Pituitary tumors are partly autonomous—they retain feedback
inhibition, but at a higher set point.
o Adrenal and ectopic tumors have autonomous hormone secretion
and do NOT (usually) exhibit feedback inhibition

20. Establishing the diagnosis
o 24-hour urinary free cortisol
o Low-dose dexamethasone suppression tests
o Midnight plasma cortisol or late-night salivary
cortisol

21. Establishing the diagnosis
o 24-hr urinary free cortisol (UFC)
o Direct assessment of circulating free (biologically active)
cortisol
o Up to 3 collections if high suspicion
o UFC >4x normal value is diagnostic (normal 3.5 to
45mcg/24 hours)

22. Establishing the diagnosis
o False negatives <6%
oAssess whether collection is complete
oIf GFR<30mls/min, UFC may be falsely low
o FP rate <4%
oRecently shown with fluid intake >5L/day

23. Establishing the diagnosis
o Low-dose Dexamethasone Suppression Test (Overnight vs 48-hr)
o AM cortisol >50nmol/L
o Excellent sensitivity but borderline specificity—false positives
oPseudo-Cushing’s
oPatient’s error in taking medication
oDrugs accelerating dexamethasone metabolism
oElevated cortisol binding globulin

24. Establishing the diagnosis
o Midnight plasma cortisol
o Level <50nmol virtually rules out the disease
o Level >130 nmol/L is diagnostic
o Late-night salivary free cortisol
o Patients collect saliva by chewing on cotton
o However, a modified cortisol assay is required so not
validated by all labs
o Excellent sensitivity and specificity—but exact cutoffs not
established

25. Establishing the diagnosis
o Differentiating between pseudo-Cushing’s and
Cushing’s syndrome
o Very difficult with co-existent depression,
alcoholism, obesity
o The dexamethasone stimulation test-Cortocotropin
releasing hormone stimulation test has shown
100% specificity and diagnostic accuracy in
differentiating.
o Spot midnight cortisol level
o Midnight/morning cortisol levels >0.67

26. Establishing the cause
o Clinical features may provide a clue
o First step is to measure plasma ACTH to differentiate ACTH-
dependent from ACTH-independent cushing’s
o If ACTH <1 pmol/L, it is an adrenal cushing’s syndrome
o If ACTH >3.3 pmol/L, it is ACTH-dependent
o If ACTH 1-3CRH stimulation is necessary

27. Establishing the cause
o ACTH-dependent
o Distinguishing pituitary from non-pituitary sources is difficult
o Carcinoids can be clinically undistinguishable from cushings
disease and are difficult to identify by imaging
o Biochemical assessment rather than imaging is used to
differentiate between pituitary and non-pituitary causes

28. Establishing the cause
o Two biochemical tests in ACTH-dependent CS
o High dose Dexamethasone Stimulation Test
o CRH stimulation test

29. o High-dose Dexamethasone Stimulation Test (DST)
oPrinciple that pituitary tumors are only partially
autonomous.
oIn contrast, adrenal and ectopic tumors are usually
autonomous.
o High dose DST x 48hrs, with baseline and final cortisol value.
Suppression >50 % suggestive of CD.
Establishing the cause

31. Establishing the cause
o Corticotropin Releasing Hormone (CRH) stimulation test
o Principle that pituitary tumors are responsive to an
exogenous dose of CRH whereas ectopic and adrenal
tumors are not
o Ovine CRH administered as an IV bolus and ACTH and
cortisol drawn at 0, 30, 60, 90, and 120 minutes.
o >50% rise in ACTH, >20% rise in cortisol
o In ectopic CS, levels are usually not altered.

32. Establishing the cause
o Adrenal CT
o In cases of ACTH-independent cushing’s syndrome
o CXR and chest CT
o In cases suggesting ectopic source
o If negative, CT abdomen, +/-pelvic, +/-neck
o Head MRI
o In cases suggesting pituitary source
o >40% of cushing’s disease have normal MRI (average size
5mm)
o 3-27% have pituitary incidentalomas

33. Cushing’s Syndrome Imaging

34. Establishing the cause
o Bilateral inferior petrosal sinus sampling is the most reliable
test to differentiate the source of ACTH and should be done in
MOST patients
o Can be avoided:
oIf a patient has ACTH dependent Cushing’s syndrome with
concordant dexamethasone stimulation test and CRH
stimulation test suggestive of cushing’s disease and an MRI
lesion >6mm

35. Inferior Petrosal Sinus Sampling (IPPS)
o The most direct way of knowing if the pituitary is making
excess ACTH is to measure it
o The inferior petrosal sinuses receive the drainage of the pituitary
gland without admixture of blood from other sources
o Each half of the pituitary drains in the ipsilateral petrosal sinus

37. Inferior Petrosal Sinus Sampling (IPSS)
o Interpretation
o Localization
oIf pituitary/periphery ratio >2 (>3 with CRH), the patient
has Cushing’s Disease
oIf pituitary/periphery ratio <1.5 (<2 with CRH), the patient
has ectopic Cushing’s Syndrome
o Lateralization
oIf the higher side/lower side >1.4/1, the tumor is on the
side with higher ACTH levels

38. Inferior Petrosal Sinus Sampling (IPPS)
o Failure to localize
o Inability to catheterize
o Incorrect catheter
placement
o Anomalous venous
drainage
o Periodic hormonogenesis
o Ectopic tumor secreting
CRH
o Failure to lateralize
o Incorrect catheter placement
o Sample withdrawal too rapid
o Midline microadenoma
o Prior transphenoidal surgery
o Ectopic tumor secreting CRH

41. Cushing’s Syndrome, Surgical Treatment
o Transphenoidal adenomectomy
o Remission rate of 80-90%, Most common surgical failures
occur with macroadenomas
o Cure is confirmed by demonstrating profound
hypoadrenalism post-op (am cortisol <50 nmol/L)
o Morbidity extremely low
o There is a period of adrenal insufficiency requiring
glucocorticoids for 6 – 8 months

42. Surgical Treatment
o Adrenal Surgery
o Laparoscopic surgery is the treatment of choice for unilateral
adrenal adenomas
o Bilateral adrenalectomy is 2nd line treatment for patients with
cushing’s disease who have not been cured by pituitary surgery
+/-radiotherapy
oPermanent need for glucocorticoids and mineralocorticoids
o15-25% risk of Nelson’s syndrome
o10% risk of recurrence due to remnant or ectopic

43. Pituitary Irradiation
o Conventional irradiation induces remission in only 20-83% of adults
o Onset of remission: 6months -5 years
o Disadvantages:
o Delayed effectiveness
o Significant risk of hypopituitarism
o Risk of neurologic and cognitive damage
o The role of newer stereotactic radiosurgery remains to be determined

44. Medical Therapy
o Uses of medical therapy
o Selected cases of Cushing’s disease prior to surgery
o In cases of cushing’s disease awaiting the effect of
radiotherapy
o Ectopic cushing’s syndrome due to an unresectable
tumor
o Adrenal carcinoma

45. Medical Therapy
o Cortisol synthesis inhibitors
o Ketoconazole
o Metyrapone
o Aminoglutethimide
o Mitotane
o Etomidate

46. Medical Therapy
o Drugs acting at the hypothalamic-pituitary level
o PPARγ agonists
o Dopamine agonists
o Somatostatin analogs
o Retinoic acid

47. Summary
o Cushing syndrome results from endogenous or exogenous
exposure to glucocorticoids; it is associated with poor
suppressibility of endogenous cortisol production with oral
dexamethasone.
o The most common cause of Cushing syndrome is the
administration of exogenous glucocorticoid therapy for another
medical condition.
o Initial tests for Cushing syndrome include the overnight low-dose
dexamethasone suppression test, 24-hour urine free cortisol, and
late-night salivary cortisol.

48. Conclusion
o Diagnosis and management of cushing’s syndrome is a challenge
o An algorithm should be closely followed to avoid misdiagnosis
o Tumour-specific surgery is the primary treatment followed by
radiotherapy and/or medical treatment
o However, treatment of cushing’s disease remains disappointing
and further developments are needed in this area

49. Sources
o Iatrogenic cushing’s syndrome in children following nasal steroid
Isaac Oludare Oluwayemi, Abiola Olufunmilayo Oduwole, Elizabeth Oyenusi,
Alphonsus Ndidi Onyiriuka, Muhammad Abdullahi, Olubunmi Benedicta Fakeye-
Udeogu, Chidozie Jude Achonwa, Moustapha Kouyate
The Pan African Medical
Journal. 2014;17:237. doi:10.11604/pamj.2014.17.237.3332
o Disorders of the adrenal cortex, Wiebke Arlt, Harrisson’s principles of internal
medicine, 19th edition, 2015, p.2940-2949
o Adrenal cortex and cushing’s syndrome, Ian B. Wilkinson, Tim Raine, Kate
Wiles, Anna Goodhart, Catriona Hall, Harriet O’Neill, P.224-225
o Endogenous Cushing Syndrome, Ha Cam Thuy Nguyen, Romesh Khardori, MD,
PhD, FACP, Catherine Anastasopoulou, MD, PhD, FACE. www.Medscape.com

50.  Late night salivary cortisol as a screening test for cushing’s syndrome.
Hershel Raff, Jonathan L. Raff, James W. Findling. Journal of clinical
endocrinology and metabolism volume 83.