Cortisol secretion is controlled by ACTH from the pituitary gland and CRH from the hypothalamus in a negative feedback loop. Cushing's disease is caused by an ACTH-secreting pituitary tumor and results in Cushing's syndrome. Diagnosis involves establishing hypercortisolemia through urine/saliva cortisol and dexamethasone suppression tests. Distinguishing pituitary vs. ectopic sources involves CRH and IPSS testing. MRI can detect pituitary tumors but small tumors are often missed. Trans-sphenoidal surgery to remove the tumor offers the best chance of remission.

1. CUSHING’S DISEASE-DIAGNOSIS
AND MANAGEMENT

2. INTRODUCTION
 Cortisol is essential for the physiological and
biochemical response to stress, both endogenous and
exogenous.
 Cortisol is secreted from the zona fasciculata, the
second layer of the adrenal cortex.
 Cortisol secretion is controlled by ACTH, which is
secreted by the anterior pituitary and is in turn
controlled by corticotropin-releasing hormone (CRH)
from the paraventricular nucleus of the hypothalamus.
 Corticotrophs in the anterior pituitary produce ACTH
and these constitute 10–20% of the cells.
 They are concentrated in the central portion of the
gland, though some cells are also present in the lateral
wings and in the pars intermedia.

5. • Corticotropin-releasing hormone secretion is
modulated by positive influences from other
parts of the brain and negative feedback from
circulating glucocorticoids.
• The afferents to the paraventricular nuclei arise
from the nucleus of the tractus solitarius, the
hypothalamus, the nucleus of the subfornical
region, the medullary reticular formation, the
locus ceruleus and the limbic system,especially
the lateral septal region.

6. Adrenocorticotropic hormone secretion is
stimulated by CRH and vasopressin;
Inhibited by negative feedback from circulating
cortisol.
CRH, ACTH and cortisol are secreted in a
periodic and rhythmic manner with the
maximum secretion at 8.00 AM and the least
at midnight.

7. • Normal Plasma Values
8 AM Cortisol: 10-25 ug/dL
4 PM Cortisol: 3-13 ug/dL
 8 AM ACTH: 10-60 pg/mL
Mean CRH : 0.77-2.5 pmol/L

8.  This diurnal variation is due to the transfer of
information about the light/dark cycle from the retina to
the paired suprachiasmatic nuclei in the hypothalamus.
 In normal humans, bursts of ACTH and cortisol secretion
occur about 15 times in a 24-hour period. ACTH levels
can vary 10-fold in a day and cortisol is actively secreted
only during one-fourth of a day.
 ACTH secretion is modulated by many
neurotransmitters.
 ACTH is stimulated by acetylcholine, serotonin and IL-1
and is inhibited by catecholamines, beta-endorphin
and dopamine.

10. CUSHING’S DISEASE VS SYNDROME
 Cushing syndrome is the set of symptoms that results
when there is a surplus of cortisol in the body.
 Cushing disease occurs when Cushing syndrome is
caused by an ACTH-producing pituitary tumor.
 Cushing syndrome can be caused by any exposure to
surplus cortisol whether it be endogenous or exogenous
while Cushing disease can only be caused by increased
cortisol levels resulting from an ACTH-producing
pituitary tumor (a specific endogenous cause).

11. Corticotroph adenomas represent
approximately 8% to 10% of all surgically
resected pituitary tumors.
Incidence- F>M.
The incidence peaks between the third and
fifth decades of life.
Although these tumors are responsible for
70% of all non-iatrogenic Cushing's syndrome
in adults, they account for only 30% of
hypercortisolemic states in children, in whom
primary adrenal tumors are more common
than Cushing syndrome.

12. CLINICAL FEATURES
Patients with corticotroph adenomas most
frequently present with endocrinopathy;less
common are symptoms due to mass effect.
Symptoms directly attributable to chronic
glucocorticoid excess.
Most conspicuous feature is :weight gain with
centripetal fat deposition,characteristic moon
facies, buffalo hump, and truncal obesity.

13. Skin thinning arising from atrophy of the
epidermis and underlying connective tissue
increases susceptibility to injury with even
minor traumaeasy bruising,plethoric
appearance and wide purple striae over the
abdomen and flanks.
Additional dermatologic findings can include
hirsutism and hyperpigmentation.

14. Metabolic and cardiac complications account
for the high mortality rates that once
accompanied Cushing's disease.
Hypertension and glucose intolerance
contribute to accelerated atherosclerosis and
other cardiovascular complications,
particularly in patients with longstanding
disease.
Osteoporosis is present to some degree in
virtually all affected patients.

15. Bone demineralization is especially prominent
in the vertebral bodies, which results in
compression fractures.
Pathologic fractures also occur elsewhere,
especially the ribs, feet, and pelvis.
Steroid myopathy leads to demonstrable
proximal myopathy on formal testing,although
only about half of all patients complain of
muscle weakness.

16. In affected women, menstrual dysfunction and
infertility result from the direct antigonadal
effect of cortisol and androgen excess.
Affected men can suffer from decreased libido
and relative infertility.

20. EVALUATION
Cardinal steps in dx of Corticotroph adenomas:
establishing hypercortisolemia.
distinguishing ACTH-dependent from ACTH-
independent causes of hypercortisolemia.
differentiating Cushing's disease from ectopic
states of ACTH excess.

21. Establishing Hypercortisolemia:
Measurement of free cortisol in a 24-hour urine
specimen is a sensitive first step in verifying the
presence of hypercortisolemia.
 An alternative is 11:00 PM measurement of the
salivary cortisol level.
Another screening test, the low-dose
dexamethasone suppression test, is also routinely
used to verify hypercortisolemia.

22. UFC(URINARY FREE CORTISOL)
It is one of the best methods for quantifying
hypercortisolism in which unmetabolised
cortisol is measured.
Urinary-free cortisol (UFC) is measured in a
carefully collected 24-hour urine sample.
The normal range is between 30 ug- 150
ug/day.
The sensitivity of the UFC method in the
diagnosis of Cushing’s syndrome is between
95% and 100%.

24. SALIVARY CORTISOL
Salivary cortisol is an ultrafiltrate of plasma
cortisol and reflects the levels of biologically
active, non-protein bound cortisol in serum.
It follows the circadian variation of serum
cortisol, with the highest levels in the morning
and lowest at midnight.
Late-night salivary cortisol (11 PM) is
commonly used as a screening test for
Cushing’s syndrome (CS).

25. An elevated late-night salivary cortisol >36
ug/dL is highly sensitive for Cushing’s
syndrome.

26. LOW-DOSE DEXAMETHASONE TEST
The low-dose dexamethasone suppression
test is a good screening procedure.
A 9.00 AM blood sample is drawn and 2 mg of
dexamethasone is given at 10.00 PM.
Blood is again drawn at 9.00 AM the next day-
cortisol is measured in both the samples.

27. The cortisol should normally be suppressed to
below 5ug/dL through negative feedback
inhibition on hypothalamus and pituitary.
In hypercortisolemic states of all causes,
sensitivity to low-dose dexamethasone
suppression is lost, and cortisol levels do not
go down.

28. • Differentiating Adrenocorticotropic Hormone–
Dependent from Adrenocorticotropic
Hormone–Independent Causes of
Hypercortisolemia:
Ordinarily, corticotroph adenomas produce only
moderate elevations of ACTH (80 to 200
pg/mL), whereas marked elevations (>200
pg/mL) are typical of ectopic ACTH-producing
lesions.

29. The secretory activity of corticotroph
adenomas, unlike that of ectopic ACTH-
producing lesions, is not autonomous.
Corticotroph adenomas retain responsiveness
to the negative feedback effects of
glucocorticoids,so in response to a sufficiently
large glucocorticoid challenge, the secretory
activity of corticotroph adenomas can be
suppressed.
This forms the basis of the high-dose
dexamethasone test.

30. HIGH-DOSE OVERNIGHT
DEXAMETHASONE SUPPRESSION TEST
 For this test,8 mg of dexamethasone is administered
orally at 11 PM and a morning (7 to 8 AM) plasma
cortisol measurement is obtained;for greatest
diagnostic accuracy, suppression of morning serum
cortisol of greater than 68% is required to assign a
diagnosis of CD(upto 50% suppression is normal).
 The sensitivity, specificity, and diagnostic accuracy of
the overnight high-dose dexamethasone test for
Cushing's disease are 89%, 100%, and 91%, respectively.

31. CRH STIMULATION TEST
Provides an additional means of distinguishing
corticotroph adenomas from ectopic ACTH-
producing lesions.
After overnight fasting and taking a baseline
sample, 100 ug of human CRH is injected
intravenously as a bolus and blood samples are
taken at 15-minute intervals up to 90 minutes.
The criteria for a positive response include a
50% increase in plasma ACTH levels or a 20%
increase in plasma cortisol levels above
baseline.

33.  Patients with Cushing’s disease exhibit a normal or
exaggerated response, whereas there is no response
with ectopic ACTH syndrome or adrenal tumours.
 Reason- Most ACTH-secreting pituitary adenomas
retain receptors for, and response to CRH, whereas
most ectopic tumors, tumors that are not derived from
pituitary tissue, do not express receptors for CRH and do
not respond to it.
 Also the hypercortisolemic state induced by the latter
renders normal pituitary corticotrophs chronically and
functionally suppressed,resistant to the stimulatory
effects of CRH.

34. IPSS SAMPLING
 If the results of the high-dose dexamethasone suppression
test and the CRH stimulation test are consistent with CD and
the pituitary MRI reveals a definite adenoma, no further
diagnostic testing is necessary.
 However, if either of these provocative endocrine tests is
inconsistent with CD and MRI fails to show an adenoma,
inferior petrosal sinus sampling is performed.
 Based on the premise that the venous drainage of
corticotroph adenomas lateralizes into the ipsilateral inferior
petrosal sinus-if a pituitary adenoma is the source of ACTH
excess, ACTH concentrations in the inferior petrosal sinus
should be higher than in the peripheral blood.

35. Simultaneously, two catheters are placed in the
inferior petrosal sinus on either side and then
obtaining serial, simultaneous samples for
central and peripheral plasma ACTH
concentrations at 2 and 0 minutes before and
at 3, 5, and 10 minutes after intravenous CRH
administration (1 μg/kg body weight).
In this test,the levels of ACTH in the primary
venous drainage of the pituitary, the inferior
petrosal sinuses, are compared to simultaneous
ACTH measurements in the peripheral blood.

36.  In patients with corticotroph adenomas, the basal
central-to-peripheral ACTH concentration gradient is
usually greater than 2.
 In patients with ectopic ACTH-producing lesions, this
gradient is less than 1.7.
 To further increase the diagnostic accuracy of this
procedure, ACTH levels are measured during CRH
stimulation; central-to peripheral gradients of greater
than 3 are diagnostic of Cushing's disease.
 When the ACTH concentration in one inferior petrosal
sinus exceeds that of the other by a factor of more
than 1.5, the adenoma is probably situated on the side
with the higher ACTH concentration.

37. Can facilitate the intraoperative identification
of adenomas that are too small to be seen on
imaging.
 Sensitivity and specificity of 96% and 100%,
respectively, for Cushing's disease and a
diagnostic accuracy of 78% with regard to
lateralization of the adenoma.

39. IMAGING
 Sella magnetic resonance imaging (MRI) is the imaging procedure of choice
for detecting and localizing the pituitary adenoma in patients with CD.
 MRI should be performed with and without contrast, as the adenomas
typically have decreased enhancement compared to the normal gland.
 The resolution of a 1.5-T magnet may reveal tumors as small as 3 mm in
diameter.
 MRI provides other important anatomical information for the surgeon:
aeration of the sphenoid, parasellar anatomy, location of the carotid arteries
or coexisting aneurysms, extent of supra- or parasellar extension of an
adenoma, and ectopic parasellar tumors.

40. Adenomas appear as hypointense defects that
become more easily discerned on gadolinium-
enhanced MRI sequences.
Incidental microadenomas, many of which are
nonfunctioning, are relatively common in the
pituitary.
 An adenoma detected on pituitary imaging
should be considered causal only if the results of
endocrine studies are fully compatible with a
diagnosis of Cushing's disease.
 Alternatively, even if the responsible tumor is not
visualized on MRI, a confirmatory endocrine
diagnosis of Cushing's disease is proof that a
corticotroph adenoma is present.

42. TREATMENT
 Trans-sphenoidal microsurgery is the treatment of choice for
CD. *
 Merits include:
• selective removal of the adenoma
• cure of hypercortisolemia
• preservation of normal glandular function.
 Identification of the adenoma and selective adenomectomy
provides remission of hypercortisolism in most patients with
an adenoma that is contained within the anterior lobe and
that is large enough to be detected by MRI.
* Tritos NA, Biller BM, Swearingen B. Management of Cushing disease. Nat
Rev Endocrinol. 2011;7(5):279–289.

43. Because most adenomas are only a few
millimeters in diameter and located deep
within the gland, finding the adenoma is
perhaps the most challenging step of the
procedure,especially when the tumor is not
visualized on preoperative imaging studies.
A careful and systematic dissection of the sellar
contents is generally required.

44.  If a tumor is not evident on opening of the dura or after
examination of all glandular surfaces, the gland must be
incised and systematically explored.
 Subtle changes in color, texture, and contour of the gland
aid in identification of an adenoma- the pseudocapsule
of a microadenoma is almost always a grey-white or
gray-yellow color.
 If no tumor is found, excisional biopsy specimens are
obtained from within the substance of the gland,
beginning with the central mucoid wedge.
 If an adenoma is not evident in the resected material,
the lateral wings of the gland are explored.

45. In an adult patient in whom an adenoma
cannot be identified and for whom fertility is
not an issue, a generous subtotal
hypophysectomy is performed at this point,
leaving only a stump of residual anterior lobe
tissue attached to the stalk.
If the adenoma remains elusive, both cavernous
sinuses and the posterior lobe must be
evaluated.

48. Durable remission follows resection in
approximately 90% of patients with
microadenomas and 50% to 60% of those with
macroadenomas.
By the second or third postoperative day, morning
cortisol levels should be less than 5μg/dL, and
serum ACTH levels should be undetectable after a
successful operation.
A postoperative morning cortisol level that persists
within the normal range, even if it represents a
dramatic decrease from the pretreatment level,
usually indicates incomplete removal and
persistent disease.

49. After successful treatment, regression of
Cushingoid features and restitution of the
pituitary-adrenal axis occur within months.*
*Newell-Price J, Trainer P, Besser M, et al. The diagnosis and differential
diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr Rev.
1998;19(5):647–672.

50. OTHER OPTIONS
When the disease is not initially cured by
surgery, several options remain:
Repeat transsphenoidal exploration
Medical therapy
Radiation therapy
Bilateral adrenalectomy

51. Radiation Therapy
For patients unresponsive to sellar exploration,
the most effective next step radiation therapy.
Remission rates of approximately 50% to 80%
after conventional radiotherapy for persistent
or recurrent Cushing's disease have been
reported.
Of patients experiencing remission, most do so
within 2 to 3 years after treatment.
Radiosurgery also offers an effective option for
refractory corticotroph adenomas.

52. Normalization of cortisol levels is observed in
70% of patients.
 Of patients achieving remission, half achieved
normalization within 1 year; in the remainder,
it was achieved within 3 years.

53. Medical Therapy
Indications:
when the sequelae of hypercortisolemia are
so debilitating that a preoperative reduction in
cortisol is necessary for optimisation before
surgery.
used to control hypercortisolemia while a
radiotherapeutic response is awaited.

56. Bilateral Adrenalectomy
Total bilateral adrenalectomy followed by
lifelong glucocorticoid and mineralocorticoid
replacement is an option of last resort, reserved
for the occasional patients in whom all other
therapies have failed:
 Already undergone multiple attempts at
transsphenoidal resection.
Patients awaiting a radiotherapeutic response
Patients intolerant of long-term
pharmacologic therapy.

57. NELSON’S SYNDROME
Nelson's syndrome is a clinical manifestation of
corticotroph adenoma or, more commonly,
progression of corticotroph adenoma after
bilateral adrenalectomy.
An iatrogenic condition, the syndrome develops in
at least 10% to 15% of patients with Cushing's
disease who undergo bilateral adrenalectomy.

58. The syndrome is easily recognizable, beginning
with a history of hypercortisolemia in which a
corticotroph adenoma was unsuspected,
undetected, or incompletely resected. Thereafter,
the hypercortisolemia was treated with bilateral
adrenalectomy, which produced temporary
remission followed by aggressive tumor growth
and the neurological sequelae of an expanding
sellar mass.
Typically, these tumors exhibit tremendous
secretory activity, producing dramatic elevations
in ACTH levels and elevations of other pro-
opiomelanocortin–related peptides, such as
melanocyte-stimulating hormone (responsible
for the hyperpigmentation that typifies the
syndrome).

59. In approximately half the patients with
Nelson's syndrome,surgical resection results in
lightening of hyperpigmentation and significant
reductions in serum ACTH levels.
For patients with disease not controlled by
surgery and without previous radiation
therapy, radiotherapy is recommended.
As many as 20% of patients eventually die of
uncontrolled local tumor growth despite the
application of all possible therapeutic
interventions.

60. THANK YOU