CHAPTER 27

CUSHING’S SYNDROME
Mary H. Samuels

1. Describe the normal function of cortisol in healthy people.

Cortisol and other glucocorticoids have many effects as physiologic regulators. They increase glucose production,
inhibit protein synthesis and increase protein breakdown, stimulate lipolysis, and affect immunologic and inflam-
matory responses. Glucocorticoids are important for maintenance of blood pressure and form an essential part
of the body’s response to stress.

2. How are cortisol levels normally regulated?

Adrenal production of cortisol is stimulated by the pituitary hormone adrenocorticotropin (ACTH). ACTH production
is stimulated by the hypothalamic hormones corticotropin-releasing hormone (CRH) and vasopressin (ADH). Corti-
sol feeds back to the pituitary and hypothalamus to suppress levels of ACTH and CRH. Under nonstress conditions,
cortisol is secreted with a pronounced circadian rhythm, with higher levels early in the morning and lower levels
late in the evening. Under stressful conditions, secretion of CRH, ACTH, and cortisol increases, and the circadian
variation is blunted. Because of the wide variation in cortisol levels over 24 hours and appropriate elevations
during stressful conditions, it may be difficult to distinguish normal secretion from abnormal secretion. For this
reason, the evaluation of a patient with suspected Cushing’s disease is often complex and confusing.

3. What are the clinical symptoms of excessive levels of cortisol?

Prolonged and inappropriately high levels of cortisol lead to Cushing’s syndrome, characterized by:
• Obesity, especially central (truncal) obesity, with wasting of the extremities, moon facies, supraclavicular fat
pads, and “buffalo hump”
• Thinning of the skin, with facial plethora, easy bruising, and violaceous striae
• Muscular weakness, especially proximal muscle weakness, and atrophy
• Hypertension, atherosclerosis, congestive heart failure, and edema
• Gonadal dysfunction and menstrual irregularities
• Psychological disturbances (e.g., depression, emotional lability, irritability, sleep disturbances)
• Osteoporosis and fractures
• Increased rate of infections and poor wound healing

4. All of my clinic patients look like they have Cushing’s syndrome. Are some clinical findings more specific for
Cushing’s syndrome than others?
Some manifestations of Cushing’s syndrome are common but nonspecific, whereas others are less common but
quite specific. The clinical findings are listed in Table 27.1, with the more specific findings listed first, followed by
the more common but less specific findings.

5. A patient presents with a history of obesity, hypertension, irregular menses, and depression. Does she have
excessive production of cortisol?
Excessive cortisol is highly unlikely. Although the listed findings are consistent with glucocorticoid excess, they are
nonspecific; most patients with such findings do not have Cushing’s syndrome (see Table 27.1). True Cushing’s
syndrome is uncommon, with an incidence of two to three cases per million people per year, although it may be
higher in patients with hypertension, diabetes, osteoporosis, or incidental adrenal masses.

6. The patient also complains of excessive hair growth and has increased terminal hair on the chin, along the
upper lip, and on the upper back. Is this finding relevant?
Hirsutism is a common, nonspecific finding in many female patients. However, it is also consistent with Cushing’s
syndrome. If it is caused by Cushing’s syndrome, hirsutism results from excessive production of adrenal andro-
gens under ACTH stimulation. Thus, hirsutism in a patient with Cushing’s syndrome is a clue that the disorder
is caused by excessive production of ACTH. (The only other condition associated with excessive production of
glucocorticoids and androgens is adrenal cancer, which is usually obvious on presentation.)

7. The patient also has increased pigmentation of the areolae, palmar creases, and an old surgical scar. Are
these findings relevant?
Hyperpigmentation is a sign of elevated production of ACTH and related peptides by the pituitary gland. It is un-
common (but possible) in Cushing’s syndrome caused by benign pituitary tumors because levels of ACTH do not
usually rise high enough to cause hyperpigmentation. It is more common in the ectopic ACTH syndrome because
213
Downloaded for enes ilerler (enesilr7@gmail.com) at Marmara University from ClinicalKey.com by Elsevier on March 30, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
 214  PITUITARY AND HYPOTHALAMIC DISORDERS

Table 27.1.  ​Symptoms and Signs of Cushing’s Syndrome.

MORE SPECIFIC, LESS COMMON MORE COMMON, LESS SPECIFIC
Easy bruising, thin skin (in young patient) Hypertension
Facial plethora Obesity/Weight gain
Violaceous striae Abnormal glucose tolerance or diabetes mellitus
Proximal muscle weakness Depression, irritability
Hypokalemia Peripheral edema
Osteoporosis (in young patient) Acne, hirsutism
Decreased libido, menstrual irregularities

ectopic tumors produce more ACTH and other peptides. The combination of Cushing’s syndrome and hyperpig-
mentation may be an indication of a serious condition.

8. What is the cause of death in patients with Cushing’s syndrome?

Patients with inadequately treated Cushing’s syndrome have a markedly increased mortality rate (two- to fivefold
above normal), usually from cardiovascular disease or infections. Hypertension, impaired glucose tolerance, dys-
lipidemia, and visceral obesity all contribute to the excess risk for cardiovascular mortality. This excess mortality
improves with adequate therapy.

9. What causes Cushing’s syndrome?

Cushing’s syndrome is a nonspecific name for any source of excessive glucocorticoids. There are four main causes,
which are further detailed in Table 27.2:
1. Exogenous glucocorticoids (ACTH independent)
2. Pituitary Cushing’s syndrome (ACTH dependent)
3. Ectopic production of ACTH (ACTH dependent)
4. Adrenal tumors (ACTH independent)

10. Of the various types of Cushing’s syndrome, which is the most common?
Overall, exogenous Cushing’s syndrome is most common. It rarely presents a diagnostic dilemma because the
physician usually knows that the patient is receiving glucocorticoids. Of the endogenous causes of Cushing’s
syndrome, pituitary Cushing’s disease accounts for about 70% of cases. Ectopic secretion of ACTH and adrenal
tumors causes approximately 15% of cases each (see Table 27.2 for frequencies).

Table 27.2.  Causes of Cushing’s Syndrome and their Relative Frequency.

ACTH DEPENDENT (80%) ACTH INDEPENDENT (20%)
Pituitary (85%) Adrenal tumors
Corticotroph adenoma Adrenal adenoma
Corticotroph hyperplasia (rare) Adrenal carcinoma (rare)
Ectopic ACTH syndrome (15%) Micronodular hyperplasia (rare)
Oat-cell carcinoma (50%) Macronodular hyperplasia (rare)
Foregut tumors (35%) Exogenous glucocorticoids (common)
Bronchial carcinoid Therapeutic (common)
Thymic carcinoid Factitious (rare)
Medullary thyroid carcinoma
Other tumors (10%)
Islet-cell tumors
Pheochromocytoma
Ectopic CRH (, 1%)
ACTH, Adrenocorticotropin; CRH, corticotropin-releasing hormone.

Downloaded for enes ilerler (enesilr7@gmail.com) at Marmara University from ClinicalKey.com by Elsevier on March 30, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
 CUSHING’S SYNDROME  215

11. Do age and gender matter in the differential diagnosis of Cushing’s syndrome?
Of patients with Cushing’s disease (pituitary tumors), 80% are women, whereas the ectopic ACTH syndrome is
more common in men. Therefore, in a male patient with Cushing’s syndrome, the risk of an extrapituitary tumor is
increased. The age range in Cushing’s disease is most frequently 20 to 40 years, whereas ectopic ACTH syndrome
has a peak incidence at 40 to 60 years. Therefore, the risk of an extrapituitary tumor is increased in an older pa-
tient with Cushing’s syndrome. Children with Cushing’s syndrome have a higher risk of malignant adrenal tumors.

12. The patient with obesity, hypertension, irregular menses, depression, and hirsutism looks like she may have
Cushing’s syndrome. What should I do?
There are three widely used screening tests for Cushing’s syndrome that have comparable sensitivity and speci-
ficity, and each can be used in the initial evaluation of a patient with suspected Cushing’s syndrome (Fig. 27.1):
1. The overnight low-dose dexamethasone suppression test: The patient takes 1 mg of dexamethasone at 11 pm
and her serum cortisol level is measured at 8 am the next morning. In healthy subjects who are not stressed,
dexamethasone (a potent glucocorticoid that does not cross-react with the cortisol assay) suppresses produc-
tion of CRH, ACTH, and cortisol. In contrast, patients with endogenous Cushing’s syndrome should not suppress
cortisol production (serum cortisol remains . 1.8 mcg/dL) when given 1 mg of dexamethasone.
2. Measurement of cortisol in saliva samples collected on two separate evenings between 11 pm and midnight:
Salivary cortisol levels are low in subjects without stress late at night but are high in those with Cushing’s
syndrome because of loss of the normal diurnal rhythm in cortisol production.
3. Urine free cortisol (UFC) levels, measured in a 24-hour collection of urine: UFC is elevated in most patients with
Cushing’s syndrome, but only a value fourfold above the normal range is diagnostic of Cushing’s syndrome
because milder elevations can be seen in stress or illness.

13. The patient had a cortisol level drawn after a 1-mg dose of dexamethasone. The level is 7 mcg/dL. Does she
have Cushing’s syndrome?
Probably not. Acute or chronic illnesses, depression, and alcohol abuse activate the hypothalamic–pituitary–
adrenal (HPA) axis because of stress and make the patient resistant to dexamethasone suppression. In fact,
because Cushing’s syndrome is so rare, a nonsuppressed cortisol level after dexamethasone is more likely to be
a false-positive result, rather than truly indicating the presence of Cushing’s syndrome. Similar limitations exist
for the other two screening tests. Further evaluation is best performed by an endocrinologist and may include
performing the alternate screening tests to see if they are concordant, as well as additional biochemical tests
(see Fig. 27.1). In some mild or cyclic cases, repeated testing over time is required to definitively diagnose
Cushing’s syndrome.

Cushing’s syndrome suspected

Exclude exogenous steroid use

Perform one of the following tests

1 mg overnight DST OR late-night salivary cortisol OR 24h urine free cortisol

Negative
Positive
Cushing’s syndrome unlikely

Confirm positive test with 1–2 additional studies

Negative
Positive
Cushing’s syndrome unlikely

Cushing’s syndrome confirmed, proceed to differential diagnosis

Fig. 27.1  ​Diagnosis of Cushing’s syndrome.

Downloaded for enes ilerler (enesilr7@gmail.com) at Marmara University from ClinicalKey.com by Elsevier on March 30, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
 216  PITUITARY AND HYPOTHALAMIC DISORDERS

14. Further biochemical testing confirms that the patient has Cushing’s syndrome. What should I do next?
After you have made the biochemical diagnosis of Cushing’s syndrome, the next step is to determine whether
she has ACTH-dependent disease or ACTH-independent disease. This distinction is made by measuring plasma
levels of ACTH. Measurements should be repeated a number of times because secretion of ACTH is variable.
Dehydroepiandrosterone sulfate (DHEAS) is an adrenal hormone that is secreted from the adrenal cortex solely
in response to stimulation by ACTH; it has a much longer half-life than ACTH and, therefore, is a useful surro-
gate marker of ACTH secretion. Recent studies have indicated that serum DHEAS measurement can provide
supportive evidence for ACTH dependence or ACTH independence in patients being evaluated for Cushing’s
syndrome.

15. The patient’s ACTH level is “normal.” Was the original suspicion of Cushing’s syndrome incorrect?
No. A normal or slightly elevated ACTH level is the usual finding in ACTH-secreting pituitary adenomas. More
marked elevations of ACTH levels suggest ectopic secretion of ACTH, although small carcinoid tumors also have
normal or mildly elevated levels of ACTH. Suppressed ACTH levels (, 10 pg/mL), in contrast, suggest a cortisol-
producing adrenal tumor. If ACTH levels are indeterminate, measurements of ACTH during stimulation with CRH
can be helpful. As discussed above, serum DHEAS levels may also be informative in this situation.

16. After the diagnosis of ACTH-dependent Cushing’s syndrome, what is the next step?
Because the most common site of excessive secretion of ACTH is a pituitary tumor, radiologic imaging of the
pituitary gland is the next step. The best study is high-resolution magnetic resonance imaging (MRI) of the
pituitary gland.

17. The pituitary MRI in the patient with ACTH-dependent Cushing’s syndrome is normal. Is the next step a search
for a carcinoid tumor, under the assumption that the pituitary is not the source of excessive ACTH?
No. At least half of pituitary MRI scans are negative in proven pituitary-dependent Cushing’s syndrome because
most corticotroph adenomas are tiny and may not be visible on MRI.

18. The pituitary MRI shows a 3-mm hypodense area in the lateral aspect of the pituitary gland. Is it time to call
the neurosurgeon?
Again, no. This finding is nonspecific; 10% of healthy adults have pituitary lesions of # 6 mm that are visible
on MRI. It is highly likely that the patient has an ACTH-secreting pituitary tumor, but the MRI does not prove this.
The MRI is diagnostic only if it shows a larger tumor (. 6 mm).

19. So, what is the next step?

One option is to proceed directly to pituitary surgery because a patient with an abnormal MRI has a 90% chance
of having an ACTH-secreting pituitary tumor. To achieve more diagnostic certainty, one has to perform bilateral
simultaneous inferior petrosal sinus sampling (IPSS) for ACTH levels. Catheters are advanced through the femoral
veins into the inferior petrosal sinuses, which drain the pituitary gland, and blood samples are obtained for ACTH
levels. If ACTH levels in the petrosal sinuses are significantly higher than those in peripheral samples, the pituitary
gland is the source of excessive ACTH. If there is no gradient between petrosal sinus and peripheral levels of
ACTH, the patient probably has a carcinoid tumor somewhere. The accuracy of the test is further increased if
ACTH responses to injection of exogenous CRH are measured. Bilateral IPSS should be performed by experienced
radiologists at referral centers.

20. IPSS shows no gradient in ACTH levels. What is the next step?
Start the search for a carcinoid tumor. Because the most likely location is the lung, computed tomography (CT) of
the lungs should be ordered. If the results are negative, CT of the abdomen should be ordered because carcinoids
also occur in the pancreas, intestinal tract, and adrenal glands.

21. IPSS shows a marked central-to-peripheral gradient in ACTH levels. What should be done next?
Transsphenoidal surgery (TSS) should be scheduled with an experienced neurosurgeon who is well versed in
examining the pituitary for small adenomas. ACTH levels from the right and left petrosal sinuses obtained during
the sampling study may tell the neurosurgeon in which side of the pituitary gland the tumor is likely to be found,
but this information is not 100% accurate.

22. What if surgery is unsuccessful?

Approximately 75% of adults with small pituitary tumors causing Cushing’s syndrome (termed Cushing’s disease)
achieve remission with TSS. However, initial remission rates are lower for macroadenomas (. 1 cm) and recur-
rence rates are significant for all tumor sizes (15%–65%). If TSS does not cure a patient with Cushing’s disease or
if it recurs, repeat TSS may be considered. Additional therapies may also be required because patients with inade-
quately treated hypercortisolism have increased morbidity and mortality rates. Of the various options after failed
surgery, none is ideal. Patients may require repeat pituitary surgery, radiation therapy, medical therapy to block
cortisol secretion or action, bilateral adrenalectomy, or a combination of these.

Downloaded for enes ilerler (enesilr7@gmail.com) at Marmara University from ClinicalKey.com by Elsevier on March 30, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
 CUSHING’S SYNDROME  217

23. What medical treatment options are available for Cushing’s syndrome?
There are three main classes of drugs for the medical treatment of Cushing’s syndrome: (1) steroidogenesis
inhibitors that block cortisol production from the adrenal gland (ketoconazole, metyrapone, mitotane, etomidate),
(2) pituitary-directed therapies to lower ACTH secretion (cabergoline, pasireotide), and (3) glucocorticoid receptor–
directed therapy to block cortisol effects on other organs (mifepristone). There are pros and cons for each drug,
including efficacy, adverse effects, costs, availability, induction of adrenal insufficiency, drug-to-drug interactions,
teratogenicity, and difficulties with monitoring and dose titration. These decisions should be made by an experi-
enced endocrinologist.

24. Why not just take out the patient’s adrenal glands?
Bilateral adrenalectomy can be safely performed via a laparoscopic approach, with low morbidity in experienced
hands. However, this leads to lifelong adrenal insufficiency and dependence on exogenous glucocorticoids and
mineralocorticoids. The other main drawback is the development of Nelson’s syndrome in approximately 20% of
patients after adrenalectomy. Nelson’s syndrome is the appearance, sometimes years after adrenalectomy, of an
aggressive corticotroph pituitary tumor. Despite these risks, bilateral adrenalectomy is a viable option for patients
who have failed initial surgery, with continued monitoring for the emergence of Nelson’s syndrome.

25. What are the correct diagnostic and treatment options for patients with ACTH-independent (adrenal) Cushing’s
syndrome?
Such patients usually have either an adrenal adenoma or carcinoma, so adrenal CT should be ordered. A mass is
usually present, and surgery should be planned. Most cases of adrenal Cushing’s syndrome are caused by benign
unilateral adrenal adenomas, which should be excised by an experienced adrenal surgeon. If the mass is obvi-
ously cancer, surgery may still help in debulking the tumor and improving the metabolic consequences of hyper-
cortisolemia. If there are multiple adrenal nodules, the patient may have a rare form of Cushing’s syndrome
(bilateral macronodular adrenal hyperplasia, primary pigmented nodular adrenal disease, Carney’s complex) and
should be evaluated by an endocrinologist. As a caveat, there is also a high prevalence of incidental, nonfunction-
ing adrenal adenomas in the general population (up to 5%) and, therefore, CT findings may not be conclusive.

26. What happens to the HPA axis after a patient undergoes successful removal of an ACTH-secreting pituitary
adenoma or a cortisol-secreting adrenal adenoma?
The HPA axis is suppressed, and the patient develops clinical adrenal insufficiency, unless he or she is given gradu-
ally decreasing doses of exogenous glucocorticoids until the HPA axis recovers. This usually requires 6 to 12 months
postoperatively. Despite the use of glucocorticoids, many patients suffer from glucocorticoid withdrawal symptoms
during this period and must be warned that this is common and expected.

27. What would be the most likely diagnosis if the original patient had all the signs of Cushing’s syndrome but
low urinary and serum levels of cortisol?
The most likely scenario is that the patient is surreptitiously or accidentally ingesting a glucocorticoid that gives
all the findings of glucocorticoid excess but is not measured in the cortisol assay. The patient and family members
should be questioned about possible access to medications, and special assays can measure the various syn-
thetic glucocorticoids.

28. Besides treatment of Cushing’s syndrome itself, what common comorbidities should be addressed in these
patients?
Diabetes associated with Cushing’s syndrome should be treated with the usual lifestyle interventions and diabetes
medications; in addition, mifepristone, a glucocorticoid receptor blocker, has been shown to reduce insulin resis-
tance, blood glucose levels, and hemoglobin A1c (HbA1c) values in patients with Cushing’s syndrome and is approved
by the U.S. Food and Drug Administration for treatment of diabetes in patients with Cushing’s syndrome. Bone
densitometry testing is advisable to detect osteopenia or osteoporosis; all patients with Cushing’s syndrome
should be advised on lifestyle measures for osteoporosis prevention (adequate intake of calcium and vitamin D
and regular exercise, as tolerated) and strong consideration should be given to the addition of osteoporosis
medications if their fracture risk is sufficiently high. Hypertension, hyperlipidemia, and glaucoma should also be
addressed as needed.

29. Should prevention of venous thromboembolic events and infectious complications also be a part of the
management plan?
Cushing’s syndrome is associated with a significantly increased risk of developing venous thromboembolism (VTE)
events. The cause appears to be an increase in plasma levels of clotting factors, especially factor VIII and Von
Willebrand factor complex and a reduction in plasma fibrinolytic activity. Patients with Cushing’s syndrome should
be evaluated for their overall VTE risk. Perioperative VTE prophylaxis is recommended in all patients and, if the VTE
risk is sufficiently high, chronic prophylaxis may be warranted until the disorder is cured or controlled.
Because of the increased risk of infections resulting from hypercortisolism, it is recommended that clinicians
discuss and offer age-appropriate vaccinations, especially those for influenza, pneumococcal pneumonia, and

Downloaded for enes ilerler (enesilr7@gmail.com) at Marmara University from ClinicalKey.com by Elsevier on March 30, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
 218  PITUITARY AND HYPOTHALAMIC DISORDERS

herpes zoster, to these patients. Prophylaxis against Pneumocystis jiroveci pneumonia (PJP) has been recom-
mended for patients receiving glucocorticoid therapy at a dose equivalent to 20 mg prednisone for 1 month or
more. Although it has not reached the level of a clinical practice recommendation, it is, nonetheless, reasonable to
consider PJP prophylaxis in patients with chronic poorly controlled Cushing’s syndrome; the antibiotics of choice
for this are sulfamethoxazole-trimethoprim, atovaquone, and dapsone.

30. Do tumors ever cause Cushing’s syndrome by making excessive CRH?

Yes. Occasionally patients who undergo TSS for a presumed corticotroph adenoma have corticotroph hyperplasia
instead. At least some of these cases are secondary to ectopic production of CRH from a carcinoid tumor in the
lung, abdomen, or other location. Therefore, levels of serum CRH should be measured in patients with Cushing’s
syndrome and corticotroph hyperplasia. If the levels are elevated, a careful search should be performed for
possible ectopic sources of CRH.

KEY PO I N T S : C U S H I N G ’ S S Y N D R O M E
• The clinical manifestations of Cushing’s syndrome can be subtle or nonspecific.
• Most patients who look like they might have Cushing’s syndrome do not.
• Screening biochemical tests for Cushing’s syndrome can be misleading, and repeated testing or more extensive
confirmatory testing is often necessary.
• Most patients with Cushing’s syndrome have a small pituitary tumor producing adrenocorticotropin.
• Patients with pituitary tumors causing Cushing’s syndrome should undergo pituitary surgery by an experienced
neurosurgeon because none of the other treatment options are ideal.

Bibliography
Carroll, T. B., & Findling, J. W. (2010). The diagnosis of Cushing’s syndrome. Reviews in Endocrine & Metabolic Disorders, 11, 147–153.
Creemers, S. G., Hofland, L. J., Lamberts, S. W., & Feelders, R. A. (2015). Cushing’s syndrome: an update on current pharmacotherapy
and future directions. Expert Opinion on Pharmacotherapy, 16, 1829–1844.
Dennedy, M. C., Annamalai, A. K., Prankerd-Smith, O., Freeman, N., Vengopal, K., Graggaber, J., Koulouri O, … Gurnell, M. (2017). Low
DHEAS: a sensitive and specific test for the detection of subclinical hypercortisolism in adrenal incidentalomas. Journal of Clinical
Endocrinology and Metabolism, 102, 786–792.
Fleseriu, M. (2012). Medical management of persistent and recurrent cushing disease. Neurosurgery Clinics of North America, 23(4),
653–668.
Fleseriu, M., Biller, B. M., Findling, J. W., Molitch, M. E., Schteingart, D. E., & Gross, C. (2012). Mifepristone, a glucocorticoid receptor
antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. Journal of Clinical Endocrinology and
Metabolism, 97, 2039–2049.
Nieman, L. K., Biller, B. M. K., Findling, J. W., Newell-Price, J., Savage, M. O., Stewart, P. M., & Montori, V. M. (2008). The diagnosis of Cushing’s
syndrome: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism, 93, 1526–1540.
Nieman, L. K., Biller, B. M. K., Findling, J. W. Murad, M. H., Newell-Price, J., Savage, M. O., & Tabarin, A. (2015). Treatment of Cushing’s
Syndrome: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism, 100, 2807–2831.

Downloaded for enes ilerler (enesilr7@gmail.com) at Marmara University from ClinicalKey.com by Elsevier on March 30, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
   e1

AbstrAct
Cushing’s syndrome is caused by excess cortisol secretion, and is characterized by central obesity, thin skin, easy
bruising, proximal muscular weakness, osteoporosis, mood disturbances, hypogonadism, and metabolic derange-
ments. These clinical manifestations may be subtle, and are often nonspecific; most patients with suspected Cushing’s
syndrome do not have it. For that reason, careful evaluation is essential for correct diagnosis. There are a number of
screening tests for Cushing’s syndrome, including late night salivary cortisol levels, 24-hour urine free cortisol levels,
and dexamethasone suppressed serum cortisol levels. Patients with untreated Cushing’s syndrome have a markedly
increased mortality rate, from cardiovascular disease and infections. Most patients with true Cushing’s syndrome have
a small pituitary tumor producing adrenocorticotropin hormone (ACTH). The optimal treatment for pituitary Cushing’s
syndrome is transsphenoidal surgery. Adjuvant medical therapies exist, but none are highly effective and free of
adverse effects.
Key Words
cortisol, adrenocorticotropin hormone (ACTH), adrenal, Cushing’s syndrome, pituitary tumor, salivary cortisol, urine free
cortisol, dexamethasone suppression test, transsphenoidal surgery, adrenalectomy, Nelson’s syndrome

Downloaded for enes ilerler (enesilr7@gmail.com) at Marmara University from ClinicalKey.com by Elsevier on March 30, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.