CUSHING’S SYNDROME

INTRODUCTION

 The symptoms and signs of Cushing's syndrome result directly from chronic
exposure to excess glucocorticoid. Establishing the diagnosis is often difficult
because none of the symptoms or signs are pathognomonic of the syndrome.
There is a large spectrum of manifestations from subclinical to overt
syndrome depending on duration and intensity of excess steroid production
 Cushing syndrome, sometimes called hypercortisolism, may be caused by the
use of oral corticosteroid medication. The condition can also occur when the
body synthesizes too much cortisol on its own
 Too much cortisol can produce some of the hallmark signs of Cushing
syndrome — a fatty hump between the shoulders, a rounded face, and pink or
purple stretch marks on the skin. Cushing syndrome can also result in high
blood pressure, bone loss and, on occasion, type 2 diabetes
Causes and pathophysiology of Cushing's
syndrome
 Cushing's syndrome may be either corticotropin (ACTH)-dependent or -
independent.
 Among all patients presenting with Cushing’s syndrome, the most common
cause is iatrogenic Cushing’s due to exogenous administration of
glucocorticoids.
 The second most common form overall is Cushing’s disease (pituitary
hypersecretion of ACTH)
 ACTH-dependent — The causes of ACTH-dependent Cushing's syndrome are associated with bila
their relative frequency is as follows:
Cushing's disease (pituitary hypersecretion of ACTH)
Ectopic secretion of ACTH by nonpituitary tumors
Ectopic secretion of corticotropin-releasing hormone (CRH) by nonhypothalamic tumors causing pit
Iatrogenic or factitious Cushing's syndrome due to administration of exogenous ACTH (not glucocor
 ACTH-independent — The causes of ACTH-independent Cushing's syndrome
are:
Iatrogenic or factitious Cushing's syndrome, which is by far the most common
cause
Adrenocortical adenomas and carcinomas
Primary pigmented nodular adrenocortical disease, also called bilateral adrenal
micronodular hyperplasia
Bilateral ACTH-independent macronodular hyperplasia
ACTH-DEPENDENT CUSHING'S SYNDROME
 The hallmark biochemical feature of ACTH-dependent Cushing’s syndrome is a
normal or elevated ACTH level, which reflects tumoral secretion. The tumor
secretion of ACTH causes bilateral adrenocortical hyperplasia and
hyperfunction . The increased serum cortisol concentrations inhibit both
hypothalamic CRH and vasopressin secretion as well as ACTH secretion by
normal pituitary corticotrophs
Cushing's disease — Almost all patients with Cushing's disease have a pituitary
adenoma. In effect, the tumor cells function at a higher than normal set point
for cortisol feedback inhibition. As the adrenal glands become increasingly
hyperplastic, they secrete proportionately more cortisol in response to a given
increment in plasma ACTH
Ectopic ACTH syndrome — Tumors of a wide variety of tissues, usually
carcinomas rather than sarcomas or lymphomas, have been associated with the
ectopic ACTH syndrome. Among them the most common are small-cell
carcinomas of the lung that, like pulmonary carcinoids and rare multiple
pulmonary tumorlets, arise from neuroendocrine cells in the distal bronchioles.
The ACTH-secreting pancreatic and thymic tumors are also carcinoid tumors that
arise from neuroendocrine cells in those tissues
 Ectopic CRH syndrome — In the ectopic CRH syndrome, CRH secretion by the
tumor causes hyperplasia and hypersecretion of the pituitary corticotrophs,
resulting sequentially in ACTH hypersecretion, cortisol hypersecretion, and
bilateral adrenal hyperplasia
ACTH-INDEPENDENT CUSHING'S SYNDROME

Primary adrenocortical hyperfunction — In Cushing's syndrome due to primary

adrenocortical disease (eg, adrenocortical tumor, micronodular dysplasia, or
ACTH-independent macronodular hyperplasia), increased cortisol secretion
suppresses both CRH and ACTH secretion, as it does in normal subjects
Most adrenocortical tumors are monoclonal, suggesting that they result from
accumulated genetic abnormalities such as activation of protooncogenes and
inactivation of tumor suppressor genes
Primary pigmented nodular adrenocortical disease — There are both sporadic
and familial forms of primary pigmented nodular adrenocortical disease, also
called bilateral adrenal micronodular hyperplasia. The familial form, Carney
syndrome or complex, is an autosomal dominant disorder characterized by two
major types of findings: pigmented lentigines and blue nevi on the face, neck,
and trunk, including the lips, conjunctivae, and sclerae; and multiple neoplasms,
both endocrine (testicular Sertoli cells and occasionally adrenal, pituitary, or
thyroid) and nonendocrine (cutaneous, mammary, atrial myxomas, and
psammomatous melanotic schwannomas)
Bilateral ACTH-independent macronodular hyperplasia — This syndrome is
associated with adrenal glands that weigh from 24 to 500 g or more and contain
multiple nonpigmented nodules greater than 5 mm in diameter. The nodules
appear to be typical benign adrenal nodules, but the internodular cortex may be
hypertrophic, rather than atrophic
The pathogenesis of bilateral macronodular hyperplasia appears to involve
overexpression of eutopic receptors, inappropriate expression of ectopic
receptors, or coupling of eutopic receptors to steroidogenic signaling pathways;
in the majority of patients, increases in cortisol secretion are mediated by
overexpression of receptors for either vasopressin, serotonin, beta-adrenergic
agonists, luteinizing hormone/chorionic gonadotropin, gastric inhibitory
polypeptide or perhaps glucagon or leptin
 Iatrogenic or factitious Cushing's syndrome — Iatrogenic or factitious
Cushing's syndrome is usually caused by administration of excessive amounts
of a synthetic glucocorticoid or compounds such as megestrol acetate , which
have some intrinsic glucocorticoid activity
 Exogenous glucocorticoids inhibit CRH and ACTH secretion, causing bilateral
adrenocortical atrophy. Plasma ACTH, serum and salivary cortisol
concentrations, and urinary cortisol excretion (unless cortisol is the steroid
administered) are all low
CLINICAL MANIFESTATIONS
 The major symptoms and signs of Cushing's syndrome are listed in the table. An
important clinical clue to the presence of glucocorticoid excess is the simultaneous
development and increasing severity of several of these symptoms
 Symptoms that are most suggestive of the presence of hypercortisolism include
supraclavicular fat pads, skin atrophy, wide purplish striae, and proximal muscle
weakness
 The relative severity of symptoms varies, being determined by the following factors:
The degree and duration of hypercortisolism
The presence or absence of androgen excess, because hypercortisolism alone causes
neither hirsutism nor pustular acne. When present in patients with pure glucocorticoid
excess (ie, adrenal adenomas), these features often pre-date the development of
Cushing’s syndrome
The cause of the hypercortisolism
Adrenal carcinoma or the ectopic ACTH syndrome can cause tumor-related symptoms
that may overshadow the effects of hypercortisolism such as weight loss instead of
weight gain
In patients with adrenal adenomas, both the degree of hypercortisolemia and many of
the clinical manifestations of Cushing's syndrome tend to be less severe in patients >50
years of age
 Progressive obesity — The most common feature of patients with Cushing's
syndrome is progressive central (centripetal) obesity, usually involving the
face, neck, trunk, abdomen and, internally, spinal canal and mediastinum.
The extremities are usually spared and may be wasted
 Fat can also accumulate in the following areas in patients with Cushing's
syndrome:
Fat accumulation in the cheeks results in a "moon" face that sometimes obscures
the ears when a patient is examined from the front. Fat deposition in the
temporal fossae also contributes to facial rounding
A "buffalo hump" or dorsocervical fat pad is common and is usually consistent
with the general degree of obesity
Enlarged fat pads that fill the supraclavicular fossae and obscure the clavicles is
one of the most specific signs of Cushing's syndrome, although they occasionally
occur in exogenous obesity. The bulging supraclavicular fat pads make the neck
appear thick and shortened. Retroorbital fat deposition may result in
exophthalmos, which is present in up to 5 percent of patients
Dermatologic manifestations
 Skin atrophy — The skin usually atrophies, the stratum corneum is thinned, and there
is loss of subcutaneous fat to a sufficient degree that subcutaneous blood vessels may
be seen. The skin eventually becomes fragile due to these changes and, in extreme
cases, peels off after being covered with adhesive tape. Minor wounds heal slowly,
and surgical wounds may dehisce
 Easy bruisability — Loss of subcutaneous connective tissue due to the catabolic effects
of glucocorticoid results in easy bruising after minimal, often unremembered injury
 Striae — Purple striae occur as the fragile skin stretches due to the enlarging trunk,
breasts, and abdomen
 Fungal infections — Cutaneous fungal infections, especially tinea versicolor, are often
found on the trunk. Some patients have fungal infections of the nails, but oral
candidiasis is rare
 Hyperpigmentation — Hyperpigmentation is induced by increased ACTH, not cortisol,
secretion. ACTH is the principal pigmentary hormone in humans. Hyperpigmentation
may be generalized, but is most conspicuous in areas exposed to light (such as the
face, neck, and back of the hands) or to chronic mild trauma, friction, or pressure
(such as the elbows, knees, spine, knuckles, waist [belt], midriff [girdle], and
shoulders [brassiere straps]). Patchy pigmentation may occur on the inner surface of
lips and the buccal mucosa along the line of dental occlusion
 Acanthosis nigricans also can be present in the axillae and around the neck
 Menstrual irregularities — Menstrual irregularities are common in women with
Cushing's syndrome
 n one series of 45 women with newly diagnosed Cushing's disease, 80 percent
had abnormal menstrual cycles; 31 percent had oligomenorrhea, 33 percent
had amenorrhea, and the remainder had excess or variable menses
 The menstrual abnormalities correlated with increased serum cortisol and
decreased serum estradiol concentrations, but not with serum androgen
concentrations. The menstrual irregularities may be due to suppression of
secretion of gonadotropin-releasing hormone by hypercortisolemia
 Signs of androgen excess in Cushing's syndrome are most common in women with
adrenal carcinomas. These tumors usually secrete large amounts of androgenic
precursors because they are inefficient at converting cholesterol to cortisol
 Androgen excess in affected women can cause the following symptoms:
Hirsutism, which is usually mild and limited to the face, but can be generalized.
Downy sideburns and increased hair on the upper lip and under the chin are most
common. The scalp hair often becomes thin, but temporal balding is rare
Oily facial skin and acne on the face, neck, or shoulders.
Increased libido
Virilization, including temporal balding, deepening voice, male body habitus, male
escutcheon, and clitoral hypertrophy, usually occurs only in girls or women with
extremely high serum concentrations of androgens due to an adrenal carcinoma
 Proximal muscle wasting and weakness — Weakness and proximal muscle
wasting are common in Cushing's syndrome, being induced by the catabolic
effects of excess glucocorticoid on skeletal muscle. Hypokalemia, due to
increased mineralocorticoid activity, can accentuate the weakness in patients
with severe hypercortisolism. On the other hand, a high-protein diet and
exercise may improve muscle wasting and increase strength
 Bone loss — Osteoporosis is common in patients with Cushing's syndrome. It is
caused by decreased intestinal calcium absorption, decreased bone
formation, increased bone resorption, and decreased renal calcium
reabsorption. The following skeletal abnormalities may be seen:
Pathologic rib and long bone fractures
Osteonecrosis (aseptic necrosis) of the femoral heads and rarely the humeral
heads
Low back pain is very common and is attributed to osteoporosis, vertebral
compression, muscle wasting, and the lordotic posture resulting from weight gain
 Glucose intolerance — Glucose intolerance is common in Cushing's syndrome.
It is primarily due to stimulation of gluconeogenesis by cortisol and peripheral
insulin resistance caused by obesity, but direct suppression of insulin release
also may contribute
Neuropsychological changes and
cognition
 Symptoms of psychiatric disease occur in over one-half of patients with Cushing's
syndrome of any etiology and are, therefore, presumably caused by excess cortisol
 The most common psychologic symptoms are:
Emotional lability
Agitated depression
Irritability
Anxiety
Panic attacks
Mild paranoia
Insomnia
 Cognition — Learning, cognition, and memory (especially short-term memory) are
impaired by hypercortisolism
 Ophthalmologic findings — Increased intraocular pressure and cataracts occur
rarely as a result of endogenous Cushing’s syndrome and are more common
with exogenous glucocorticoid administration, in particular, topical steroids
 Infection and immune function — Glucocorticoids inhibit immune function,
thereby contributing to an increased frequency of infections. The mechanism
by which glucocorticoid excess predisposes to infection is poorly understood.
One mechanism may be a fall in circulating CD4 cells and decline in natural
killer-cell activity. Inhibition of cytokine release has another clinically
important effect with regard to infection: the associated reduction in
inflammatory and febrile responses to bacterial infection may make these
infections difficult to detect
 Men with Cushing syndrome may experience
Decreased libido
Decreased fertility
Erectile dysfunction
Establishing the diagnosis of Cushing's
syndrome
 Daily urinary cortisol excretion — Twenty-four hour urinary cortisol excretion
provides a direct and reliable practical index of cortisol secretion
 Low-dose dexamethasone suppression tests — Exogenous dexamethasone
substitutes for endogenous cortisol in suppressing ACTH release. The
dexamethasone doses used should reliably suppress ACTH secretion by the
normal pituitary gland, leading to suppression of cortisol secretion and
subsequent reductions in serum cortisol concentrations and urinary excretion
of cortisol and cortisol metabolites
 Late evening salivary cortisol — A late evening salivary cortisol concentration
can be used to establish the diagnosis of Cushing's syndrome. Saliva is easily
collected and cortisol is stable in saliva even at room temperature for several
days. Saliva collection has the distinct advantage of being noninvasive, and can
be performed by the patient at home
 Plasma ACTH — Plasma ACTH concentrations are normally between 20 and 80
pg/mL (4.5 and 18 pmol/L) at 8 AM. The values fall during the waking hours
and are usually less than 20 pg/mL (4.5 pmol/L) at 4 PM and less than 10
pg/mL (2.2 pmol/L), usually less than 5 pg/mL (1.1 pmol/L), within one hour
after the usual time of falling sleep
 In theory, plasma ACTH should be measured between about 11 PM and
midnight or at bedtime
 CRH stimulation test — Most patients with Cushing's disease respond with
ACTH and cortisol increases within 45 minutes after the intravenous
administration of corticotropin-releasing hormone. Patients with adrenal
tumors with increased urinary free cortisol and most with ectopic ACTH-
secreting tumors do not respond because pituitary ACTH secretion is
suppressed
 Vasopressin stimulation test — Vasopressin or desmopressin (dDAVP) also
stimulates ACTH release in most patients with Cushing's disease and usually
induces a response similar to that of CRH; when given with CRH it can
improve sensitivity in Cushing's disease
 Petrosal venous sinus catheterization — The most direct way to demonstrate
pituitary ACTH hypersecretion is to document a central-to-peripheral ACTH
gradient in the blood draining the tumor. The petrosal venous sinus drains the
pituitary via the cavernous sinus
 To perform this procedure, catheters are inserted via the jugular or femoral
veins into both inferior petrosal veins. It is important that each catheter be in
the proper location, not in the jugular bulb or vein, because of the large
dilution factor produced by blood returning from other areas of the cranium
Imaging studies
 The diagnosis of Cushing's syndrome and its cause lie entirely in the domain of
the endocrine laboratory. Imaging procedures provide no information about
function and are useful only for tumor localization
 Pituitary MRI — Unenhanced and gadolinium-enhanced high-resolution MR
images of the sella turcica should be obtained before petrosal sinus sampling
to exclude a tumor more than 6 mm in size, which might obviate the need for
venous sampling. The procedure also is indicated before transsphenoidal
exploration to document the anatomy of the sella turcica
 MRI is more sensitive than CT in detecting corticotroph adenomas, but still
detects only about 50 percent of these tumors. Dynamic MRI (ie, obtaining
images very rapidly after gadolinium administration) or spoiled gradient
recalled acquisition MRI techniques may provide slightly greater sensitivity
than conventional MRI, but yield more false-positive scans
 Pituitary imaging is not necessary in patients in whom endocrine testing
suggests ectopic ACTH secretion
Overview of the treatment of Cushing's
syndrome
 GENERAL PRINCIPLES — Ideal therapy of Cushing's syndrome would achieve the
following goals:
Reverse the clinical manifestations by reducing cortisol secretion to normal
Eradicate any tumor threatening the health of the patient
Avoid permanent dependence upon medications
Avoid permanent hormone deficiency
 In individual patients, however, one or more of the last three goals may have to
be sacrificed to achieve the essential first goal. The therapeutic protocols
described below proceed from permanently curing the disorder by resecting or
ablating its cause to merely controlling the hypercortisolism in patients in whom a
cure cannot be achieved
 Each stage in the treatment should provide maximum probability of cure with the
least chance of permanent endocrine deficiency or other undesirable side effects
 During this time, treatment of co-morbidities such as hypertension, osteoporosis,
and diabetes should be instituted, and the use of medications to prevent
thrombosis or bone loss should be considered
 EXOGENOUS CUSHING'S SYNDROME — The treatment of Cushing's syndrome
due to exogenous therapy is to stop the glucocorticoid. Most patients who
have taken enough glucocorticoid for a long enough time to cause Cushing's
syndrome will have a period of hypothalamic-pituitary adrenal insufficiency
when therapy is discontinued. Thus, gradual withdrawal is necessary
 Transsphenoidal surgery — The treatment of choice for Cushing's disease is
transsphenoidal microadenomectomy when a clearly circumscribed
microadenoma can be identified at surgery
 Medical therapy — Although the hypercortisolism of Cushing’s disease is
primarily treated surgically, medical therapy is often required when surgery is
delayed, contraindicated, or unsuccessful. Adrenal enzyme inhibitors are the
most commonly used drugs, but adrenolytic agents, drugs that target the
pituitary, and glucocorticoid-receptor antagonists also have been used.
Medical therapy targeting the corticotroph tumor such as cabergoline or
pasireotide can result in normalization of 24-hour urinary free cortisol in 20 to
40 percent of them, especially if they have only mild hypercortisolism
 Pituitary irradiation — For patients in whom fertility is an important concern
and in whom a tumor is not found or who are not cured by transsphenoidal
resection of a tumor, pituitary irradiation is one of the next treatment
options; it may also be considered as primary therapy for children under age
18
 Maximum benefit is usually achieved within six to 12 months, but may require
two to three years, and during this time period hypercortisolism should be
controlled with one or several adrenal enzyme inhibitors
 Adrenalectomy — Bilateral total adrenalectomy with lifelong daily
glucocorticoid and mineralocorticoid replacement therapy is the final
definitive cure, and may be preferred by some patients instead of radiation
therapy. In one series, laparoscopic adrenalectomy was successful in 42
patients with Cushing's disease who had not been cured by previous pituitary
surgery, radiotherapy and/or medical therapy
 Glucocorticoid antagonists — The glucocorticoid (as well as progestin)
antagonist mifepristone (RU 486) was used successfully for nine weeks in one
patient
 Somatostatin analogues — Octreotide , a long-acting analogue of
somatostatin, rapidly reduces ectopic ACTH secretion by some nonpituitary
tumors, but does not usually reduce tumor size. Uptake of 111-In-
pentetreotide by the tumor also predicts a positive response to the drug. The
agent may be given either as a twice daily or monthly injection and is
expensive. It therefore has limited value in treating patients with the ectopic
ACTH syndrome
 Ectopic CRH secretion — Ectopic CRH secretion is a very rare disorder, having
been proved in only a small number of cases, mostly with fairly well-
differentiated pulmonary carcinoid tumors. The treatment and prognosis of
this condition is the same as for ectopic ACTH secretion. The Cushing's
syndrome can easily be controlled, but the ultimate prognosis depends upon
the malignancy of the tumor and whether it can be completely resected
 COURSE AFTER EFFECTIVE THERAPY — Physical symptoms and signs of
Cushing's syndrome disappear gradually over a period of two to 12 months.
Hypertension and glucose intolerance improve but may not disappear
 The osteoporosis of Cushing's syndrome begins to improve about six months
after the hypercortisolemia is cured, improves rapidly during the ensuing two
years, and more gradually thereafter, but may not normalize
COMPLICATIONS

 Without treatment, complications of Cushing syndrome may include:

Bone loss (osteoporosis), which can result in unusual bone fractures, such as rib
fractures and fractures of the bones in the feet
High blood pressure (hypertension)
Type 2 diabetes
Frequent or unusual infections
Loss of muscle mass and strength
PROGNOSIS

 Untreated Cushing's syndrome is often fatal, with most deaths being due to
cardiovascular, thromboembolic, or hypertensive complications or bacterial or
fungal infections. Years ago there was a 50 percent mortality five years after the
development of symptoms, but the prognosis is much better now
 Cushing's disease is virtually always curable, although rarely patients may die of
perioperative or other complications. No patient with Cushing's syndrome of any
cause should die from persistent hypercortisolism, since cortisol production can
always be controlled by adrenal enzyme inhibitors, mitotane , or adrenalectomy
 However, patients with ectopic ACTH secretion or adrenocortical carcinoma may
have a poor prognosis associated with the underlying tumor. In addition, patients
with severe Cushing's syndrome may die from opportunistic infections before
completion of diagnostic studies. Increased coagulability is also associated with
deep vein thrombosis, pulmonary edema, and myocardial infarction
EPIDEMIOLOGY
 Estimates of the incidence of Cushing's syndrome are imprecise and
underestimate the incidence of iatrogenic Cushing's syndrome, undiagnosed
mild hypercortisolism, and the ectopic ACTH syndrome
 Iatrogenic Cushing's syndrome — More than 10 million Americans receive
pharmacologic doses of glucocorticoids each year, so iatrogenic Cushing's
syndrome must be more common than any other cause, but is seldom
reported
 Ectopic ACTH syndrome — This is probably the second most common cause of
Cushing's syndrome, but is often not diagnosed. About 1 percent of patients
with small-cell lung cancer have ectopic ACTH syndrome; small-cell lung
carcinoma causes half of all cases of the syndrome
 Cushing's disease — Pituitary ACTH-dependent Cushing's syndrome is five to
six times more common than Cushing's syndrome caused by benign and
malignant adrenal tumors combined. Thus the incidence of Cushing's disease
may be 5 to 25 per million per year
 Adrenal tumors — Adrenal masses are discovered incidentally at autopsy or by
radiographic studies in 1.3 to 8.7 percent of adults, more than 99 percent of
whom do not present with symptomatic adrenal disease. Adrenal carcinoma
and adenoma cause a similar number of cases of Cushing's syndrome in most
series
 Women are three to eight times more likely than men to develop Cushing's
disease, about three times more likely to have either benign or malignant
adrenal tumors, and about four to five times more likely to have Cushing's
syndrome associated with an adrenal tumor
 The age at which the ectopic ACTH syndrome develops parallels the
development of lung carcinoma, increasing rapidly after age 50 years. Ectopic
ACTH secretion due to carcinoid tumors can occur at earlier ages but is rare in
children
The end

 Thank you all