Clinics in Dermatology (2006) 24, 260 – 265

Cushing’s syndrome
Amal Shibli-Rahhal, MD, Marta Van Beek, MD, Janet A. Schlechte, MD*

Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Department of Dermatology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA

Abstract Cushing’s syndrome results from prolonged exposure to excess glucocorticoids. Patients with
Cushing’s syndrome may develop multiple metabolic problems including obesity, hyperglycemia,
hypertension, depression, low bone mass, muscle atrophy, and hypogonadism. Cutaneous manifes-
tations of hypercortisolism include skin atrophy, excessive bruising, purple striations, poor wound
healing, facial plethora, vellous hypertrichosis and hirsutism. Diagnostic tests used to screen for
Cushing’s syndrome include 24-hour urine cortisol, the 1 mg dexamethasone suppresion test, and late
night salivary cortisol. A normal screening test excludes the diagnosis of Cushing’s. Patients with an
abnormal screening test should be referred to an endocrinologist for complete evaluation of the pituitary-
adrenal axis.
D 2006 Elsevier Inc. All rights reserved.

Introduction patients demonstrate periods of excess cortisol production

Cushing’s syndrome is the eponym applied to the symp-
toms and physical findings that develop after prolonged
exposure to glucocorticoids. The most common cause of
Cushing’s syndrome is the administration of pharmacologic
doses of oral, parenteral or rarely, topical glucocorticoids.1
Endogenous glucocorticoid excess may arise from an adre-
nocorticotropic hormone (ACTH)–secreting pituitary tumor,
ectopic (nonpituitary) ACTH production, or adrenal tumor
(Fig. l). In all patients with Cushing’s syndrome, there is
loss of diurnal variation of ACTH and cortisol secretion,
leading to sustained hypercortisolism.
Pituitary and adrenal tumors causing Cushing’s syndrome
occur more frequently in women, whereas ectopic ACTH
production is more common in men.2 Cushing’s syndrome
is uncommon in children, where it usually presents with
growth retardation and weight gain after puberty.3 Rare
* Corresponding author. Department of Internal Medicine, University
of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
E-mail address: janet-schlechte@uiowa.edu (J.A. Schlechte).
interspersed with periods of normal cortisol secretion
(periodic Cushing’s).4
Making the diagnosis of Cushing’s syndrome is difficult
because no one physical finding is pathognomonic and
many of the symptoms and physical findings occur in a
large percentage of the general population. In this chapter,
we will discuss the clinical presentation and diagnostic
approach to Cushing’s syndrome, with special emphasis on
glucocorticoids and the skin.
Clinical presentation
With a few exceptions, it is not possible to determine the
cause of Cushing’s syndrome from the clinical presentation.
In patients with pituitary tumors, symptoms develop over
years, whereas those with ectopic ACTH production may
note the abrupt onset of symptoms. Patients with ectopic
ACTH production are less likely to be obese and commonly
present with muscle weakness and hypokalemia. Feminiza-
tion and virilization are usually only seen in patients with

0738-081X/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.clindermatol.2006.04.012
Cushing’s syndrome
Fig. 1 Schematic representation of the different causes of
Cushing’s syndrome.
adrenal carcinoma. Benign intracranial hypertension, glau-
coma, posterior subcapsular cataracts, pancreatitis, and
avascular necrosis of the bone are virtually unique to
patients taking pharmacologic doses of steroids.5
Cutaneous manifestations
The classic cutaneous manifestations of Cushing’s
syndrome are facial plethora, acne, purpura, cutaneous
atrophy, hirsutism, vellous hypertrichosis, and wide purplish
striae over the abdomen, flanks, and upper arms.6 The
epidermis assumes a paper-like appearance, and the skin
becomes thin, translucent, and bruises easily. The skin is
Fig. 2 Characteristic wide purple-colored striae on the abdomen
and flanks of a patient with Cushing’s syndrome.
261
widely atrophic, and ecchymoses (or purpura) are more
common in areas subject to minor trauma, such as the arms
and legs. Such easy bruising is a result of poor dermal
support, loss of collagen, and decreased elasticity. Small
blood vessels may also be visible under the skin (telangi-
ectasias) and dilated because of weakness of the vessel walls
and the surrounding connective tissue.7 The thinning of
the epidermis and its underlying connective tissue leads to
the plethoric appearance and the slow healing of wounds
and abrasions.8 The striae seen on the abdomen, thighs, and
arms vary in width and length and are a result of atrophic
scarring secondary to dermal tears (Fig. 2). The character-
istic purple color of striae results from the translucency
of the skin, which makes underlying vascular structures
more visible.9,10
Histologically, cutaneous atrophy is manifested by thin-
ning of the epidermis and flattening of the dermoepidermal
junction with a concomitant decrease in dermal ground
substance and interfibrillar spaces between collagen and
elastin, which leads to collapse of the extracellular matrix
and reorientation of the collagen and elastin fibers.11-13
These effects are a consequence of glucocorticoid-mediated
inhibition of type I and III collagen synthesis and reduction
of hyaluronic acid content of the skin.
Women with Cushing’s syndrome may develop male
pattern baldness and/or excess hair on the face, extremities,
and abdomen. Vellus hypertrichosis presents as excess
terminal hair growth on the upper lip and chin or as diffuse
overgrowth of vellus hairs on other areas of the body. Oily
skin and acne are common in women with pituitary Cushing’s
and may be related to the peripheral conversion of cortico-
steroids to androgens.14 Severe hirsutism, temporal balding,
deepening of the voice, male body habitus, and clitoral
hypertrophy are almost exclusively seen in women with
adrenal carcinoma and arise from excessive production of
androgen precursors by the tumor.
Hyperpigmentation only occurs in ACTH-dependent
Cushing’s (pituitary or ectopic), and is mediated by the action
of ACTH on melanocyte-stimulating receptors.15 The pig-
Fig. 3 Centripetal obesity. Also seen are wide purple striae.
262
mentation is generalized but more obvious in areas exposed
to sunlight, friction, or trauma. Traumatic and iatrogenic scars
that form in the presence of elevated levels of plasma ACTH
can remain permanently pigmented, whereas those present
before ACTH secretion increases are not pigmented. Hyper-
pigmentation does not occur in patients with adrenal tumors
as high levels of cortisol suppress ACTH production.
Patients with Cushing’s syndrome are at increased risk of
cutaneous infections from the immunosuppressive effect
of glucocorticoids. Cutaneous staphylococcal, candidal,
and superficial fungal infections are extremely common.
Malassezia furfur causes tinea versicolor in this population
and presents as hyper- or hypopigmented scaly macules
over the central chest and upper back. Dermatophytes
such as Trichophyton rubrum can cause infections of
the nails (onychomycosis), the skin of the feet (tinea pedis),
or the skin of the trunk and/or extremities (tinea corporis).
Opportunistic infections, such as deep fungal infections
with aspergillus, zygomycosis, or phaeohyphomycosis may
also occur.16,17
Obesity
Except for patients with ectopic ACTH production,
weight gain is a prominent symptom in all patients with
glucocorticoid excess. It is accompanied by fat deposition in
the abdomen, mediastinum, face, and neck, and it is the
distribution of fat in the cheeks, posterior cervical and
temporal areas, and abdomen, which leads to the well-known
findings of buffalo hump, moon facies, and centripetal
obesity (Fig. 3). Fat deposition in the supraclavicular fossae
obscures the clavicles and makes the neck appear thick
and short. Because supraclavicular and posterior cervical
fat deposition is commonly seen in obese patients without
glucocorticoid excess, these findings are not diagnostic
of Cushing’s syndrome.3,9,18-21 In rare cases, patients with
Cushing’s syndrome develop exophthalmus because of retro-
orbital fat deposition.22
Muscle atrophy/weakness
Muscle weakness involving the proximal muscles of the
lower extremities and the shoulder girdle occurs in up to two
thirds of patients with Cushing’s and is a consequence of the
catabolic effect of glucocorticoids on skeletal muscle. The
muscle weakness can be exacerbated by physical inactivity
and hypokalemia and is a common presenting symptom in
patients with the ectopic ACTH syndrome.23 Lower
extremity weakness develops before upper extremity weak-
ness and is usually more severe. Muscle atrophy is present
in less than one third of the patients, but it is one of the most
specific signs of Cushing’s syndrome.14
Skeletal effects
Low bone mass occurs in 50% to 60% of patients with
glucocorticoid excess, and patients may develop fractures in
the feet, ribs, and vertebrae.4,9,18-21 The loss of bone mineral
A. Shibli-Rahhal et al.
is more severe at the lumbar spine than the hip, and vertebral
compression fractures are seen in 20% to 30% of patients.24
The bone loss develops because high levels of glucocorti-
coids impair intestinal calcium absorption, suppress bone
formation, and accelerate bone resorption.25 Because of the
effects of glucocorticoids on calcium absorption, calcium
and vitamin D replacement is vital in patients with
Cushing’s. After successful treatment of Cushing’s syn-
drome, bone mineral density improves and may normalize.26
Although virtually all patients with Cushing’s syndrome
eventually develop bone loss, only those receiving pharma-
cologic doses develop avascular necrosis.27 Low back pain
may develop because of vertebral compression fractures,
muscle wasting, and/or the lordotic posture that accompanies
weight gain.
Psychiatric symptoms
Emotional and cognitive symptoms are frequent in
patients with Cushing’s syndrome and range from depressed
mood to mania and dysphoria. Most patients experience
increased irritability and mood swings, decreased concen-
tration, and impaired memory.3,9,18-21 Insomnia occurs early
in the course of the disease and may be due to the loss of the
diurnal variation and subsequent high serum cortisol
concentrations during sleep.28 Depression is the most
commonly encountered psychiatric disorder in patients with
Cushing’s syndrome and occurs in two thirds. Patients
usually present with increased appetite and weight gain, but
suicidal ideation has been reported in severe cases.29,30
Children with Cushing’s syndrome become euphoric or
manic, particularly early in the course of the illness. Mania
is more common with exogenous glucocorticoid use,
whereas depression is mostly observed in the setting of
endogenous Cushing’s.31 Psychiatric abnormalities may not
resolve completely after correction of hypercortisolism.30,32
Effect on reproductive system
Hypercortisolism has a direct inhibitory effect on the
hypothalamus and pituitary, leading to suppression of
gonadotropin-releasing hormone as well as follicle-stimu-
lating hormone and luteinizing hormone. This leads to
gonadal dysfunction in both sexes, usually manifesting as
decreased libido. Menstrual abnormalities including amen-
orrhea, oligomenorrhea, and menorrhagia occur in 80% of
women.33-35 The hypogonadism in both sexes is usually
reversible once the hypercortisolism is successfully treated.
Diabetes/hyperglycemia
Although frank diabetes is uncommon, glucose intoler-
ance is seen in 50% of patients with Cushing’s.3,9,18-21 High
levels of cortisol stimulate gluconeogenesis and aggravate
peripheral insulin resistance. Poorly controlled blood glu-
cose in an obese patient with diabetes may be the first clue
to the presence of Cushing’s syndrome, and Cushing’s syn-
drome is present in 3% of obese patients with poorly
Cushing’s syndrome
controlled diabetes.36 Hyperglycemia can be treated with
oral hypoglycemic agents in some patients, whereas others
require treatment with insulin. Hyperglycemia secondary to
cortisol excess becomes easier to control and may resolve
after treatment of hypercortisolism.
Hypertension and cardiovascular disease
Patients with Cushing’s syndrome are at increased risk
for cardiovascular disease and hypertension. The hyperten-
sion may be related to glucocorticoid-induced vascular
damage, increased peripheral vascular responsiveness, or
activation of the renin-angiotensin system.10,37 In severe
hypercortisolism, the ability of the kidney to inactivate
cortisol is overwhelmed, leading to activation of mineral-
ocorticoid receptors. This is usually observed in patients
with ectopic ACTH production.10,38,39 Like hyperglycemia,
hypertension becomes easier to control and may resolve
when Cushing’s syndrome is treated. Although patients
with Cushing’s may present with peripheral edema, heart
failure is an uncommon complication of the disease. The
combination of glucose intolerance, hypertension, and
cardiovascular disease is responsible for the increased
morbidity and death in patients with Cushing’s syndrome.40
Thrombotic events
Thrombophlebitis and thromboembolic events develop in
some patients with Cushing’s syndrome secondary to
increased plasma concentrations of clotting factors and
decreased fibrinolytic activity. This problem has been
reported in 10% to 20% of the patients, and prophylactic
anticoagulation perioperatively has been found to decrease
the risk of thromboembolism.41
Infections
The mechanism by which glucocorticoid excess predis-
poses to infection is poorly understood but is, in part,
secondary to suppression of cellular immunity.9,18 Patients
with Cushing’s syndrome may present with reactivation of
tuberculosis, and cutaneous and systemic fungal and oppor-
tunistic infections may occur.18,42,43 Opportunistic infec-
tions are more common in patients with the ectopic ACTH
syndrome who usually have more severe hypercortisolism.
Because these patients may not mount a febrile response, the
clinical diagnosis of an infectious process may be difficult.
Making the diagnosis of Cushing’s syndrome
The first step in the evaluation of a patient with signs and
symptoms of glucocorticoid excess is a careful history and
physical examination, and a review of old photographs, if
available. The next step is to confirm the presence of hyper-
cortisolism. A reliable test to establish the presence of
hypercortisolism is crucial because obesity, weight gain, and
hypertension are so common in the general population.
263
Because of its diurnal variation and pulsatile secretion, a
random serum cortisol is not adequate to document gluco-
corticoid excess. Three good screening tests are available.
Twenty-four–hour urine cortisol
The test requires an accurate 24-hour urine collection and
has a diagnostic sensitivity and specificity between 95% and
l00%. The reference range depends on the type of assay
used. With high-performance liquid chromatography, the
upper limit of normal is 40 to 50 lg in 24 hours. The test
should not be used in patients with abnormal renal function,
and patients with chronic anxiety, depression, alcoholism, or
eating disorders may have falsely elevated levels.3,10,19,44 A
normal 24-hour urine cortisol excludes the diagnosis of
Cushing’s syndrome.
Dexamethasone 1 mg (overnight) suppression test
This test is performed by administering l mg of
dexamethasone orally at 11 pm, followed by measurement
of serum cortisol at 8 am the following day. The test
has a sensitivity of 90% to 100% but a low specificity
(41%).3,10,19,44 False-positive results are seen in patients
taking estrogen or anticonvulsants and in patients with
depressive illness. Marked obesity and severe stress may
also lead to a false-positive result. When measured by
radioimmunoassay, an 8 am serum cortisol level of less than
5 lg/dL excludes the diagnosis of Cushing’s syndrome. If
cortisol is measured by an immunometric assay, a level of
lower than 1.8 lg/dL should be used.45 - 47
Late night salivary cortisol
The first abnormality in the pituitary adrenal axis in
patients with Cushing’s is the loss of circadian rhythm and is
the rationale for measurement of nighttime cortisol as a
screening test. This test is performed by collecting saliva
with a specially designed pledget between 11:00 pm and
midnight. The reference range varies, depending on the
assay used; however, a level higher than 0.25 lg/dL is
diagnostic of Cushing’s syndrome.3,10,19,44,48 The test has
a sensitivity of 90% to 95% and a specificity of 90% to
100%. Experience with salivary cortisol measurement is
not as extensive as with the other screening tests but it
is easy to perform, and data suggest a clear separation bet-
ween patients with Cushing’s syndrome and those with
normal adrenal function.48
If the screening test is normal, glucocorticoid excess is
excluded, and the patient does not have Cushing’s syn-
drome. If the results of a screening test are equivocal or if
the test is negative in the setting of a high clinical suspicion
of glucocorticoid excess, the test should be repeated.10
When the diagnosis of glucocorticoid excess is estab-
lished, the next step is to determine whether the hyper-
cortisolism is due to a pituitary, adrenal, or ectopic source.
Beyond the screening test, formal evaluation of the pituitary-
adrenal axis should be performed by an endocrinologist.
264
A discussion of the diagnostic tests involved in establishing
the cause of the disorder is beyond the scope of this chapter.
Therapy
Cardiovascular mortality is 4 times higher in patients
with Cushing’s syndrome, compared with the general
population, so early recognition and treatment are extremely
important.40 With an ACTH-secreting pituitary tumor, the
therapy of choice is transsphenoidal pituitary surgery. The
success rate of this procedure is variable and largely
dependent on the experience of the surgeon and on the
size of the tumor. The surgical approach is not always
successful, and pituitary irradiation or focused radiosur-
gery may be necessary.20 When an adrenal tumor is the
cause of Cushing’s syndrome, unilateral adrenalectomy is
required. Chemotherapy is sometimes used with malignant
tumors not amenable to surgery.49 The therapy for ectopic
ACTH syndrome involves treatment of the underlying
malignancy. Medical therapy, especially inhibitors of
cortisol synthesis, plays an important role in treatment of
ectopic ACTH syndrome.49
Conclusion
Cushing’s syndrome results from prolonged exposure to
excessive amounts of glucocorticoids. Endogenous Cush-
ing’s syndrome arises from ectopic or pituitary ACTH pro-
duction or from an adrenal adenoma or carcinoma secreting
cortisol. Hypercortisolism leads to multiple metabolic dis-
turbances, weight gain, muscle weakness, bone loss, hypo-
gonadism, depression, glucose intolerance, and hypertension.
Hypercortisolism also alters the synthesis of key skin
components, leading to atrophy, plethora, striae, bruising,
and poor wound healing.
The diagnosis of Cushing’s syndrome requires a careful
history and physical examination, followed by screening
and localization studies. Available screening tests include
a 24-hour urinary cortisol, an overnight (l mg) dexameth-
asone suppression test, and a late night salivary cortisol.
A normal screening test excludes the diagnosis of
Cushing’s syndrome.
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