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Further Reading
1 Nawar R, Aron D. Adrenal incidentaloma—a continuing management dilemma. Endocr Relat
Cancer 2005; 12: 585–98.
2 Dluhy RG, Maher MM, Wu C-L. Case 7—2005: a 59-year-old woman with an incidentally
discovered adrenal nodule. N Engl J Med 2005; 352: 1025–32.
3 Terzolo M, Bovio S, Pia A, et al. Midnight serum cortisol as a marker of increased cardiovascular
risk in patients with a clinically inapparent adrenal adenoma. Eur J Endocrinol 2005; 153:
307–15.
4 Reznik Y, Lefebvre H, Rohmer V, et al; REHOS study group. Aberrant adrenal sensitivity to
multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol
hypersecretion: a prospective clinical study. Clin Endocrinol 2004; 61: 311–19.
5 Tenenbaum F, Groussin L, Foehrenbach H, et al. 18F-fluorodeoxyglucose positron emission
tomography as a diagnostic tool for malignancy of adrenocortical tumours? Preliminary results
in 13 consecutive cases. Eur J Endocrinol 2004; 150: 789–92.

P R O B L E M

14 Cushing’s Syndrome

Case History
LB is a 40-year-old female schoolteacher. She has noticed weight gain, hirsutism and a
tendency to bruise easily. These symptoms have been developing over the past 3 years. She
has sought advice on a number of occasions and thinks, having researched her symptoms
on the internet, that she may have Cushing’s syndrome. A random serum cortisol is
elevated at 700 nmol/l (normal 250–450 nmol/l).
How should she be investigated further?
At what stage should she be referred to hospital?
She would like to know what treatment she may require.
What is her prognosis?

Background
Investigation of a patient with suspected Cushing’s syndrome frequently proves to be
challenging. Furthermore, although sometimes difficult to diagnose, it is a condition that
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Table 14.1 Differential diagnosis of Cushing’s syndrome

Per cent of cases

ACTH dependent Pituitary adenoma 70

Ectopic ACTH secretion 10
Ectopic CRH secretion ⬍1

ACTH independent Adrenal adenoma 10

Adrenal carcinoma 8
Macronodular hyperplasia 1
Micronodular hyperplasia ⬍1

ACTH ⫽ adrenocorticotrophic hormone; CRH ⫽ corticotrophin-releasing hormone.

is often even more difficult to exclude. The first step is always to confirm that cortisol
excess is present, and that cortisol production is not under normal control. This is easily
done with the combination of urine free cortisol measurements, and an overnight dexa-
methasone suppression test (DST, with 1 mg dexamethasone). Further evaluation is
indicated if the plasma cortisol fails to suppress below 50 nmol/l. In patients who are
severely obese, depressed or have high alcohol intake plasma cortisol may fail to suppress
adequately. The DST works on the principle that adrenocorticotrophic hormone
(ACTH) production from a basophil adenoma will suppress with steroid but the thresh-
old is higher than for normal pituitary tissue. Patients with ectopic ACTH or adrenal
lesions show no change in ACTH levels. Cortisol suppression during a low-dose DST can
occur, particularly if the Cushing’s is cyclical.
Cushing’s is relatively rare with an estimated incidence of 2–3 per million per year. It
should be suspected in patients who present with bruising, round face, central obesity,
hirsutism, proximal myopathy, striae, hypertension and glucose intolerance. The presen-
tation is variable and it may take up to 5 years for patients to develop full-blown features
of the syndrome. Patients with early-onset osteoporosis (age ⬍ 65 years) and with adre-
nal tumours should be screened. A differential diagnosis of Cushing’s syndrome is pre-
sented in Table 14.1.
Once a state of cortisol excess is confirmed, and that it is ACTH dependent, the next
investigations of choice are a prolonged DST and a corticotrophin-releasing hormone
(CRH) test (Figure 14.1).1 Performed together, these tests have virtually 100% sensitivity
in detecting pituitary-driven Cushing’s. Differences in test protocols, doses of dexa-
methasone, and the methods used to measure cortisol in different centres, along with the
fact that no test performed alone even approaches 100% sensitivity and specificity, has
given rise to uncertainty about which is the best test protocol. Care should be taken to
distinguish between high-dose and prolonged DSTs. Some prefer to do the DST in a two-
stage procedure where 1 mg dexamethasone is given to start with and then 8 mg is given
on the following day or on a separate occasion. This protocol has the advantage of being
shorter and lending itself to outpatient management. However, it has a sensitivity of only
68%, although it is virtually 100% specific, and there are inconsistencies between results
of this test and the low-dose DST. Our preference is for a prolonged test where the patient
is given 0.5 mg dexamethasone every 6 hours for 48 hours. This can be preceded by
48 hours of measuring diurnal cortisol and 24-hour urine free cortisol (UFC). Ectopic
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14 Cushing’s syndrome 65

O/N DST
Urine free cortisol

No
Cushing’s syndrome Reinvestigate at 3/12
confirmed? If clinical suspicion high

Yes

Measure ACTH

<1.1pmol/l 1.1–3.3pmol/l >3.3pmol/l

ACTH independent indeterminate ACTH dependent

CT/MRI adrenals High-dose DST MRI pituitary

CRH test

Cushing’s disease confirmed?

Yes No

Work up for surgery IPSS

CT/MRI chest, abdomen, pelvis

111In-octreotide scan

Ectopic ACTH

Fig. 14.1 Investigation of Cushing’s syndrome. The first step is always to confirm the presence of cortisol excess,
then to determine whether or not it is adrenocorticotrophic hormone (ACTH) dependent. In borderline cases,
where there is a high index of suspicion, screening tests may have to be performed on multiple occasions. CRH ⫽
corticotrophin-releasing hormone; DST ⫽ dexamethasone suppression test; IPSS ⫽ inferior petrosal sinus sampling.

ACTH secretion most commonly comes from small cell lung tumour, pancreatic carcinoma,
or from carcinoid tumours.
The CRH test formerly used ovine CRH but human CRH is now generally used (1 ␮g
per kg or 100 ␮g is administered intravenously). The ACTH and cortisol is checked at
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baseline and for 60–75 minutes after. In Cushing’s disease, ACTH increases by at least
35% and cortisol by at least 20%. Performed alone, the test has a sensitivity of between
70% and 90% for diagnosis of pituitary Cushing’s. There is no response of either ACTH
or cortisol in patients with ectopic ACTH secretion or Cushing’s due to an adrenal lesion.
The metyrapone test can be performed if there are difficulties with access to CRH, or in
cases where there is diagnostic doubt. Metyrapone is an inhibitor of the enzyme 11␤-
hydroxylase. Administration of the drug leads to increased ACTH and cortisol precursors
in patients with Cushing’s disease. The desmopressin test is occasionally of use. The hor-
mone, acting through its V2 and V3 receptors stimulates ACTH, and therefore cortisol,
secretion in patients with Cushing’s disease.
Magnetic resonance imaging (MRI) is the imaging method of choice for corti-
cotroph adenomas. The lesions are hypodense and do not enhance, and MRI is only
70% sensitive. Lesions less than 6 mm may not be detected. A further difficulty is that
up to 10% of the normal population have incidental pituitary adenomas, making it all
the more important to be certain about the biochemical diagnosis before trying to
interpret imaging studies and plan management. The technique of inferior petrosal
sinus sampling (IPSS) is now widely available. It is highly accurate but technically
demanding. It also carries risk of brain stem vascular damage, venous thrombosis pul-
monary embolism and cranial nerve palsy. It is best used when there is proven ACTH-
dependent Cushing’s that may be due to ectopic ACTH secretion or where there is
doubt whether a pituitary tumour is functioning. A ratio of central to peripheral ACTH
in excess of 3.0 following CRH injection is diagnostic of basophil adenoma, and distin-
guishes Cushing’s disease from other hypercortisolaemic states with a high degree of
accuracy (sensitivity and specificity of 94%). Contrary to previous claims, it is unreli-
able in lateralizing tumour. Jugular venous sampling is safer and less technically
demanding, but much less sensitive. Sampling from the cavernous sinus has also been
advocated but carries high risk.
Transsphenoidal surgery is the treatment of choice for Cushing’s disease, and leads to
remission in 70–90% of cases. In cases with persistent or recurrent disease, repeat surgery
leads to remission in 70%. Successful treatment is more likely with small tumours and if
the lesion has been identified pre- or peri-operatively. Following successful removal there
is a dramatic decrease in cortisol production and the patient requires careful weaning off
steroid replacement as endogenous ACTH production recovers. This process can take up
to 18 months, during which careful monitoring is required. Medical treatment may be
useful in patients in preparation for surgery, or where surgery cannot be performed.
Metyrapone has been the most commonly used drug. Ketoconazole is also widely used—
this drug blocks the P450SCC, 17,20 desmolase, 11␤-hydroxylase, and the 17␣-hydroxylase
enzymes. Aminoglutethimide, mitotane, trilostane, and etomidate have all been used.
Radiotherapy is useful in patients in whom surgery has failed or cannot be performed.
The effect may be slow, necessitating interim medical therapy, and there is a high inci-
dence of pituitary hormone deficiencies in the longer term.

Recent Developments
1 Silent corticotroph adenomas (SCA) are pituitary tumours that are not associated
with clinical features of Cushing’s disease, even though they are positive for ACTH on
immunostaining.2 Following surgery, up to a third of these tumours recur and up to a
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14 Cushing’s syndrome 67

fifth of patients with SCA go on to develop hypercortisolism. There is an argument

for treating them with combined surgery and radiotherapy.
2 Although rare, nodular adrenal disease should be considered in the differential diag-
nosis of ACTH-independent Cushing’s.3 This disorder may be part of genetic syn-
dromes including MEN type I, McCune–Albright syndrome, and the Carney
complex. Cortisol secretion continues in the face of suppressed ACTH, and may be
driven by other hormonal and neuroendocrine stimuli including vasopressin and gas-
tric inhibitory polypeptide. The treatment of choice is surgical.
3 To date, long-term drug treatment of Cushing’s has not been an option because of
lack of complete effectiveness of drugs and the high incidence of side effects.4 The
drug RU-486 is a combined glucocorticoid, androgen and progesterone receptor
blocker and has shown promise in preliminary studies. Other drugs of potential use
in both decreasing ACTH secretion and inhibiting tumour growth are retinoic acid
and peroxisome proliferator-activated receptor (PPAR)-␥ agonists.
4 The recent review of 20 years’ experience at the National Institutes of Health provides
valuable information.5 The authors confirmed the utility of IPSS for establishing the
diagnosis. It is common to fail to localize the lesion initially, in which case the most
likely diagnosis is pulmonary carcinoid. Survival rate is particularly poor in patients
with small cell lung tumour, medullary thyroid carcinoma and gastrinoma.
5 Recovery following, even successful, treatment of Cushing’s may take some time.
Recently, quality of life has been assessed in series of patients with cured Cushing’s.6
Patients scored low on measures of fatigue, anxiety, depression, and other aspects of
health and wellbeing. Development of hypopituitarism following treatment was a
strong predictor of poor health. The duration of the illness prior to diagnosis, the
need for surgery and the demands of follow-up may all be factors.

Conclusions
Investigation of suspected Cushing’s syndrome should be carried out in stages. As
Cushing’s is relatively rare, we recommend that patients be referred at an early stage. The
tests always need to be interpreted in the light of the clinical picture. There is, at present,
no satisfactory medical treatment for the long-term treatment of Cushing’s syndrome.
The commonest diagnosis (70%) is Cushing’s disease and the treatment of choice for this
is surgery via a transsphenoidal route. Immediate re-operation is indicated for those who
fail to respond immediately. With modern treatment and careful monitoring of the need
for replacement hormones, the prognosis is very good, although many patients take up to
2 years to return to a normal, or near-normal, state of health.

Further Reading
1 Lindsay JR, Nieman LK. Differential diagnosis and imaging in Cushing’s syndrome. Endocrinol
Metab Clin North Am 2005; 34: 403–21.
2 Baldeweg SE, Pollock JR, Powell M, Ahlquist J. A spectrum of behaviour in silent corticotroph
pituitary adenomas. Br J Neurosurg 2005; 19: 38–42.
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3 Lacroix A, Bourdeau I. Bilateral adrenal Cushing’s syndrome: macronodular adrenal

hyperplasia and primary pigmented nodular adrenocortical disease. Endocrinol Metab Clin
North Am 2005; 34: 441–58.
4 Heaney AP. Novel medical approaches for the treatment of Cushing’s disease. J Endocrinol Invest
2004; 27: 591–5.
5 Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK. Cushing’s syndrome due to ectopic
corticotrophin secretion: 20 years’ experience at the National Institutes of Health. J Clin
Endocrinol Metab 2005; 90: 4955–62.
6 Van Aken MO, Pereira AM, Biermasz NR, et al. Quality of life in patients after long-term
biochemical cure of Cushing’s disease. J Clin Endocrinol Metab 2005; 90: 3279–86.

P R O B L E M

15 Congenital Adrenal Hyperplasia

Case History
A 29-year-old woman seeks advice because of her embarrassing facial hirsutism. Her
general health is good and she does not take any medications. Her sister has previously
been diagnosed with congenital adrenal hyperplasia. She wonders whether she may also
have this condition and if it is likely to affect her chances of becoming pregnant and
whether it may affect her children.
How should the diagnosis be confirmed or excluded?
If she has the condition, what is the best approach to treatment?
Will it affect her chances of becoming pregnant?
What are the chances of a child being affected?

Background
Congenital adrenal hyperplasia (CAH) is group of autosomal recessively inherited condi-
tions where genes coding for one of the enzymes in the pathway leading to cortisol syn-
thesis are defective. 21-hydroxylase deficiency is by far the commonest form, accounting
for 95% of cases of CAH.1 Defective production of cortisol and aldosterone with over-
production of adrenal androgens due to shunting of precursor steroids into the adrenal
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