CUSHING’S SYNDROME

Department of Endocrinology, Zhongda hospital,

Institute of Diabetes, Medical School
Southeast University
Cushing’s syndrome

• Cushing’s syndrome reflects a constellation of clinical features that result

from chronic exposure to excess glucocorticoids of any etiology.
• The disorder can be ACTH-dependent (e.g. pituitary corticotrope adenoma,
ectopic secretion of ACTH by nonpituitary tumor) or ACTH-independent
(e.g., adrenocortical adenoma, adrenocortical carcinoma, nodular adrenal
hyperplasia), as well as iatrogenic (e.g., administration of exogenous
glucocorticoids to treat various inflammatory conditions).
• The term Cushing’s disease refers specifically to Cushing’s syndrome
caused by a pituitary corticotrope adenoma.
 REGULATORY CONTROL OF STEROIDOGENESIS

• Glucocorticoid synthesis is under inhibitory feedback

control by the hypothalamus and the pituitary (Fig. 406-2).
• Hypothalamic release of corticotropin-releasing hormone
(CRH) occurs in response to endogenous or exogenous
stress.
• CRH stimulates the cleavage of the 241–amino acid
polypeptide proopiomelanocortin (POMC) by pituitary-
specific prohormone convertase 1 (PC1), yielding the 39–
amino acid peptide ACTH.
• ACTH is released by the corticotrope cells of the anterior
pituitary and acts as the pivotal regulator of adrenal
cortisol synthesis, with additional shortterm effects on
mineralocorticoid and adrenal androgen synthesis.
 REGULATORY CONTROL OF STEROIDOGENESIS

• The release of CRH, and subsequently ACTH, occurs in

a pulsatile fashion that follows a circadian rhythm
under the control of the hypothalamus, specifically its
suprachiasmatic nucleus (SCN), with additional
regulation by a complex network of cell-specific clock
genes.
• Reflecting the pattern of ACTH secretion, adrenal
cortisol secretion exhibits a distinct circadian rhythm,
starting to rise in the early morning hours prior to
awakening, with peak levels in the morning and low
levels in the evening
Epidemiology

• Cushing’s syndrome is generally considered a rare disease.

• It occurs with an incidence of 1–2 per 100,000 population per year.
However, it is debated whether mild cortisol excess may be more prevalent
among patients with several features of Cushing’s such as centripetal
obesity, type 2 diabetes, and osteoporotic vertebral fractures, recognizing
that these are relatively nonspecific and common in the population.
 Etiology
• In at least 90% of patients with Cushing’s disease,
ACTH excess is caused by a corticotrope pituitary
microadenoma, often only a few millimeters in diameter.
• Pituitary macroadenomas (i.e., tumors >1 cm in size)
are found in only 5–10% of patients. Pituitary
corticotrope adenomas usually occur sporadically but
very rarely can be found in the context of multiple
endocrine neoplasia type 1 (MEN 1).
• The majority of patients with ACTH-independent
cortisol excess harbor a cortisol-producing adrenal
adenoma; intratumor mutations, i.e., somatic mutations
in the PKA catalytic subunit PRKACA, have been
identified as cause of disease in 40% of these tumors.
• Adrenocortical carcinomas may also cause ACTH-
independent disease and are often large, with excess
production of several corticosteroid classes.
 Clinical Manifestations
• Glucocorticoids affect almost all cells of the body, and thus
signs of cortisol excess impact multiple physiologic systems
with upregulation of gluconeogenesis, lipolysis, and protein
catabolism causing the most prominent features.
• In addition, excess glucocorticoid secretion overcomes the
ability of 11β-HSD2 to rapidly inactivate cortisol to cortisone
in the kidney, thereby exerting mineralocorticoid actions,
manifest as diastolic hypertension, hypokalemia, and edema.
• Excess glucocorticoids also interfere with central regulatory
systems, leading to suppression of gonadotropins with
subsequent hypogonadism and amenorrhea, and suppression
of the hypothalamic-pituitary-thyroid axis, resulting in
decreased thyroidstimulating hormone (TSH) secretion.
 Clinical Manifestations
• The majority of clinical signs and symptoms observed in Cushing’s syndrome are relatively
nonspecific and include features such as obesity, diabetes, diastolic hypertension, hirsutism, and
depression that are commonly found in patients who do not have Cushing’s.
• Therefore, careful clinical assessment is an important aspect of evaluating suspected cases.
• A diagnosis of Cushing’s should be considered when several clinical features are found in the same
patient, in particular when more specific features are found. These include fragility of the skin, with
easy bruising and broad (>1 cm), purplish striae , and signs of proximal myopathy, which becomes
most obvious when trying to stand up from a chair without the use of hands or when climbing stairs.
• Clinical manifestations of Cushing’s do not differ substantially among the different causes of
Cushing’s.
• In ectopic ACTH syndrome, hyperpigmentation of the knuckles, scars, or skin areas exposed to
increased friction can be observed and is caused by stimulatory effects of excess ACTH and other
POMC cleavage products on melanocyte pigment production.
• Furthermore, patients with ectopic ACTH syndrome, and some with adrenocortical carcinoma as
the cause of Cushing’s, may have a more brisk onset and rapid progression of clinical signs and
symptoms.
Clinical Manifestations
 Diagnosis

• A diagnosis of Cushing’s can be considered as established if the results of several tests are
consistently suggestive of Cushing’s.
• These tests may include increased 24-h urinary free cortisol excretion in three separate collections,
failure to appropriately suppress morning cortisol after overnight exposure to dexamethasone, and
evidence of loss of diurnal cortisol secretion with high levels at midnight, the time of the
physiologically lowest secretion.
• Factors potentially affecting the outcome of these diagnostic tests have to be excluded such as
incomplete 24-h urine collection or rapid inactivation of dexamethasone due to concurrent intake of
CYP3A4-inducing drugs (e.g., antiepileptics, rifampicin).
• Concurrent intake of oral contraceptives that raise CBG and thus total cortisol can cause failure to
suppress after dexamethasone. If in doubt, testing should be repeated after 4–6 weeks off estrogens.

Patients with pseudo-Cushing states, i.e., alcohol-related, and those with cyclic Cushing’s may require
further testing to safely confirm or exclude the diagnosis of Cushing’s.
Diagnosis
 Differential Diagnosis

• Generally, plasma ACTH levels are suppressed in cases of autonomous adrenal cortisol excess, as a
consequence of enhanced negative feedback to the hypothalamus and pituitary.
• By contrast, patients with ACTH-dependent Cushing’s have normal or increased plasma ACTH,
with very high levels being found in some patients with ectopic ACTH syndrome.
• Importantly, imaging should only be used after it is established whether the cortisol excess is ACTH-
dependent or ACTH-independent, because nodules in the pituitary or the adrenal are a common
finding in the general population.
• In patients with confirmed ACTH-independent excess, adrenal imaging is indicated , preferably
using an unenhanced computed tomography (CT) scan. This allows assessment of adrenal
morphology and determination of precontrast tumor density in Hounsfield units (HU), which helps
to distinguish between benign and malignant adrenal lesions.
 TREATMENT

• Overt Cushing’s is associated with a poor prognosis if left untreated. In ACTH-independent disease,
treatment consists of surgical removal of the adrenal tumor. For smaller tumors, a minimally
invasive approach can be used, whereas for larger tumors and those suspected of malignancy, an
open approach is preferred.
• In Cushing’s disease, the treatment of choice is selective removal of the pituitary corticotrope tumor,
usually via an endoscopic transsphenoidal approach. This results in an initial cure rate of 70–80%
when performed by a highly experienced surgeon. However, even after initial remission following
surgery, long-term follow-up is important because late relapse occurs in a significant number of
patients.
• If pituitary disease recurs, there are several options, including second surgery, radiotherapy,
stereotactic radiosurgery, and bilateral adrenalectomy. These options need to be applied in a highly
individualized fashion.
 TREATMENT

• In some patients with very severe, overt Cushing’s (e.g., difficult to control hypokalemic
hypertension or acute psychosis), it may be necessary to introduce medical therapy to rapidly control
the cortisol excess during the period leading up to surgery.
• Similarly, patients with metastasized, glucocorticoid-producing carcinomas may require long-term
antiglucocorticoid drug treatment. In case of ectopic ACTH syndrome, in which the tumor cannot be
located, one must carefully weigh whether drug treatment or bilateral adrenalectomy is the most
appropriate choice, with the latter facilitating immediate cure but requiring life-long corticosteroid
replacement. In this instance, it is paramount to ensure regular imaging follow-up for identification
of the ectopic ACTH source.
• Oral agents with established efficacy in Cushing’s syndrome are metyrapone and ketoconazole.
Metyrapone inhibits cortisol synthesis at the level of 11β-hydroxylase , whereas the antimycotic drug
ketoconazole inhibits the early steps of steroidogenesis. Typical starting doses are 500 mg tid for
metyrapone (maximum dose, 6 g) and 200 mg tid for ketoconazole (maximum dose, 1200 mg).
 TREATMENT

• Mitotane, a derivative of the insecticide o,p’DDD, is an adrenolytic agent that is also effective for
reducing cortisol. Because of its side effect profile, it is most commonly used in the context of
adrenocortical carcinoma, but low-dose treatment (500–1000 mg/d) has also been used in benign
Cushing’s. In severe cases of cortisol excess, etomidate can be used to lower cortisol. It is
administered by continuous IV infusion in low, nonanesthetic doses.
• After the successful removal of an ACTH- or cortisol-producing tumor, the HPA axis will remain
suppressed. Thus, hydrocortisone replacement needs to be initiated at the time of surgery and slowly
tapered following recovery, to allow physiologic adaptation to normal cortisol levels. Depending on
degree and duration of cortisol excess, the HPA axis may require many months or even years to
• resume normal function.