CushingsDiseaseGuidelines.

Writtenby:DrChristinaDaousi,SeniorLecturer/ConsultantEndocrinologist
Agreedby:MerseysideandCheshireNeurooncologyCNG,December2012
Forreview:December2014

CORTICOTROPH PITUITARY ADENOMAS (CUSHINGS DISEASE)

The Diagnostic Pathway (11-2K-234)

Common presenting symptoms:

Reddish/purple striae
Facial plethora
Proximal muscle weakness/proximal myopathy
Bruising
Unexplained osteoporosis
Centripetal Obesity
Dorsocervical fat pad (buffalo hump)
Facial fullness
Supraclavicular fullness
Thin skin
Acne
Peripheral oedema
Hirsutism
Depression
Hypertension
Diabetes mellitus
Menstrual irregularity
Hypokalaemia

Clinical and Biochemical assessment:

Complex endocrine syndrome

Series of tests in a logical sequence, attention to potential pitfalls

Initial testing to confirm hypercortisolism (Cushings syndrome)

Urine free cortisol (UFC) (at least 2 measurements)

1-mg overnight dexamethasone suppression test (DST)
Longer low-dose DST (2 mg/day for 48 hours)

ACTH measurement

ACTH < 10pg/ml (2 pmol/L) at 0900 h with concomittant increased production of cortisol
suggest an ACTH-independent cause of CS
ACTH > 20 pg/ml (4pmol/L) suggest an ACTH-dependent cause

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CushingsDiseaseGuidelines.Writtenby:DrChristinaDaousi,SeniorLecturer/ConsultantEndocrinologist
Agreedby:MerseysideandCheshireNeurooncologyCNG,December2012
Forreview:December2014

Differentiating between pituitary driven Cushings (Cushings Disease-CD) and ectopic ACTH
secretion:

High dose dexamethasone suppression test

Sensitivity 60-80%
Good specificity when a cut-off of cortisol suppression > 80 % is used

CRH test

Radiological assessment:

All patients with a suspected corticotroph adenoma should have a MRI scan as per current WCFT
imaging protocol for pituitary tumours which includes the following sequences:
-T2 axial brain images
-T1 sagittal and coronal images of pituitary
-Post gadolinium T1 sagittal and coronal images of pituitary

If conventional MR imaging is negative then Dynamic Pituitary MRI should be performed as per
current WCFT protocol which includes the following sequences:
-T2 axial Brain images
-T1 Coronal Pituitary images
-T1 Coronal Dynamic Post Gadolinium
-T1 Coronal/Sagittal Post Gadolinium
-T2 Coronal High resolution images of. Pituitary
-T1 Coronal delayed Post Gadolinium images

Things to consider following radiological assessment:

Discrete pituitary adenoma is found in 35-60% of patients with CD.

Size of the tumour < 5 mm in half of the cases
> 10 mm in only a fifth of cases of imaging positive CD
10% of normal people harbour pituitary incidentalomas but most are < 6 mm
Classic clinical presentation, dynamic testing compatible with pituitary Cushings syndrome
(CS), the presence of a focal lesion > 6 mm may provide a definitive diagnosis and no further
evaluation may be required.

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CushingsDiseaseGuidelines.Writtenby:DrChristinaDaousi,SeniorLecturer/ConsultantEndocrinologist
Agreedby:MerseysideandCheshireNeurooncologyCNG,December2012
Forreview:December2014

Inferior Petrosal Sinus Sampling (IPSS)

Reserved for cases of ACTH-dependent CS where clinical, biochemical and radiological

studies are discordant or equivocal.
Overall sensitivity of 85-97%
Specificity 95-99%
The absence of a significant inferior petrosal sinus to peripheral (IPS:P) ACTH ratio does not
imply ectopic secretion of ACTH nor does it exclude Cushings disease

False negative results

Anomalous venous drainage
Hypoplastic inferior petrosal sinus

False positive results

Treatment that leads to normocortisolaemia
Periodic hormonogenesis in ectopic CS
Ectopic CRH-ACTH secretion
ACTH-secreting pituitary adenomas in the sphenoid sinus

IPSS for localization of pituitary microadenomas

Controversial
Interpetrosal sinus ratio > 1.4 has been suggested as consistent with ipsilaeteral localization
of a corticotroph adenoma
Accuracy 75% using findings at pituitary surgery as the gold standard
Some of the cases of mis-lateralization can be explained by anomalous venous drainage
The results of lateralization when performing IPSS cannot be relied upon in patients with CD
who have asymmetric drainage

MRI & IPSS

IPSS accurately localizes the pituitary lesion more frequently than imaging studies (70% vs
49%)
When MRI is normal, IPSS localizes the lesion in 89%
When the two tests disagree, IPSS is more commonly correct.
When the two tests agree, however, both are sometimes wrong.

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CushingsDiseaseGuidelines.Writtenby:DrChristinaDaousi,SeniorLecturer/ConsultantEndocrinologist
Agreedby:MerseysideandCheshireNeurooncologyCNG,December2012
Forreview:December2014

All patients to be put through the Regional Pituitary MDT

The Treatment Pathway (11-2K-235)

Transsphenoidal selective adenomectomy:

- Optimal treatment is surgical resection by selective adenomectomy

-Careful sectioning through the pituitary gland may be required to locate the tumour, because some
tumours have an identifiable pseudocapsule, whereas others do not exhibit a discrete border between
the tumour and normal pituitary tissue
-If a discrete microadenoma cannot be located by sellar exploration, total or partial hypophysectomy
may be indicated (lower remission rate and higher complication and hypopituitarism rates)

Favourable prognostic factors associated with successful adenomectomy:

-pre-operative detection of the microadenoma by MRI
-a well-defined tumour that is not invading either the basal dura or cavernous sinus
-histological confirmation of an ACTH-secreting tumour
-low postoperative serum cortisol levels
- longlasting adrenal insufficiency post-surgery

In patients with a macroadenoma, remission rates are lower, recurrence rates higher and recurrence
also occurs sooner than in those with a microadenoma.

Persistent Disease after Transsphenoidal Surgery

In the event of failure after initial pituitary surgery or relapse after a period of remission, a choice of
second line therapeutic options needs to be discussed with the patient, including repeat pituitary
surgery, radiotherapy, or bilateral adrenalectomy.

Pituitary surgery for persistent or recurrent disease

-Remission rates lower than that seen after the first operation and higher rates of hypopituitarism
-Remission rates are higher if an adenoma is located
-Improved success rates are achieved in patients with radiologically detectable tumours

-Repeat transsphenoidal surgery for residual disease as soon as active, persistent disease is evident.
A delay of 46 wk may be required to confirm the need for re-operation because of continued partial
improvement in cortisol levels after the initial surgery.

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CushingsDiseaseGuidelines.Writtenby:DrChristinaDaousi,SeniorLecturer/ConsultantEndocrinologist
Agreedby:MerseysideandCheshireNeurooncologyCNG,December2012
Forreview:December2014

Conventional fractionated radiotherapy and stereotactic radiosurgery

Remission rates 50-60% within 3-5 years
Long-term follow-up is necessary to detect relapse, which can occur after an initial response
to both types of radiotherapy.

Bilateral adrenalectomy

Definitive cure
Lifelong glucocorticoid and mineralocorticoid replacement therapy
25% risk of Nelsons syndrome

Medical Treatment

Agents that act at hypothalamic-pituitary level (dopamine agonists-cabergoline)

Tumour-directed medical therapy (new somatostatin analogue pasireotide)
Inhibitors of cortisol secretion at adrenal level (Inhibitors of steroid biosynthesis):
-Metyrapone (monotherapy and combination, side effects (S/E): acne, hypertension,
hirsutism, nausea
-Ketoconazole (monotherapy and combination, benign spectrum of S/E, severe hepatitis
1:1500, initial daily dose 400-600 mg max 1600 mg)

The Follow Up Pathway (11-2K-236)

To minimise duplication of clinic appointments, biochemical testing and MRI scans the
following is proposed:
A joint neurosurgery / neuro-endocrinology clinic appointment is desirable this minimises
clinic appointments and avoids duplication of follow-up imaging and follow up pituitary
function testing
MRI may not be required during the initial post-operative follow-up period as the majority of
corticotroph adenomas are microadenomas and many are not radiologically evident before
TSS
MRI is the modality of choice for follow up in patients with macroadenomas and persistent
disease, and should be performed as per current WCFT imaging protocol for pituitary tumours

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CushingsDiseaseGuidelines.Writtenby:DrChristinaDaousi,SeniorLecturer/ConsultantEndocrinologist
Agreedby:MerseysideandCheshireNeurooncologyCNG,December2012
Forreview:December2014

Once biochemical control of the disease has been established following the appropriate
treatment modalities, follow-up could be transferred and / or shared with the patients local
hospital-based Endocrinology team. Follow-up should be life-long.
Referral back to the joint neurosurgery / neuro-endocrinology clinic and the regional Pituitary
MDT can take place at any time during the follow-up pathway when evidence of recurrent
disease emerges

Biochemical assessment of disease control:

Post-operative serum cortisol

-Persistent postoperative morning serum cortisol levels < 50 nmol/L are generally associated with
remission and a low recurrence rate of approximately 10% at 10 years
-Persistent serum cortisol level above 140 nmol/liter for up to 6 wk requires further evaluation
-If serum cortisol levels are between 50-140 the patient can be considered in remission and can be
observed without additional treatment for Cushings disease

24-h UFC
-UFC values below the lower end of the normal range of the assay used to measure UFC suggest
remission
-values in the normal range are equivocal
-values above the normal range indicate persistent tumour and disease activity

Glucocorticoid Replacement
Tumour resection leads to corticosteroid deficiency because the remaining normal
corticotroph cells have been suppressed by longstanding hypercortisolism. Hypocortisolism
provides an index of surgical success.
Glucocorticoid withdrawal symptoms (e.g. fatigue, nausea, and joint aches) should be
anticipated in all patients; hypocortisolism and symptoms are managed with physiological
glucocorticoid therapy until the axis recovers.
Replacement therapy can be stopped when the morning cortisol level or the cortisol response
to tetracosactide 250 mcg (Short Synacthen Test; SST) is > 500 nmol/l.

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CushingsDiseaseGuidelines.Writtenby:DrChristinaDaousi,SeniorLecturer/ConsultantEndocrinologist
Agreedby:MerseysideandCheshireNeurooncologyCNG,December2012
Forreview:December2014

REFERENCES

1. Nieman LK, Biller BM, Findling JW et al. The diagnosis of Cushing's syndrome: an
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;
93(5):1526-1540.

2. Lindsay JR, Oldfield EH, Stratakis CA, Nieman LK. The postoperative basal cortisol
and CRH tests for prediction of long-term remission from Cushing's disease after
transsphenoidal surgery. J Clin Endocrinol Metab 2011; 96(7):2057-2064.

3. Daousi C, Nixon T, Javadpour M, Hayden K, Macfarlane IA. Inferior petrosal sinus

ACTH and prolactin responses to CRH in ACTH-dependent Cushing's syndrome: a
single centre experience from the United Kingdom. Pituitary 2010; 13(2):95-104.

4. Biller BM, Grossman AB, Stewart PM et al. Treatment of adrenocorticotropin-

dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 2008;
93(7):2454-2462.

5. Aghi MK. Management of recurrent and refractory Cushing disease. Nat Clin Pract
Endocrinol Metab 2008; 4(10):560-568.

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CushingsDiseaseGuidelines.Writtenby:DrChristinaDaousi,SeniorLecturer/ConsultantEndocrinologist
Agreedby:MerseysideandCheshireNeurooncologyCNG,December2012
Forreview:December2014

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