Hindawi
International Journal of Endocrinology
Volume 2017, Article ID 1547358, 6 pages
https://doi.org/10.1155/2017/1547358
Review Article
Screening for Cushing Syndrome at the Primary Care Level:
What Every General Practitioner Must Know
Ernest Yorke,1 Yacoba Atiase,1 Josephine Akpalu,1 and Osei Sarfo-Kantanka2
1Endocrine & Diabetes Unit, Department of Medicine and Therapeutics, School of Medicine and Dentistry, College of Health Sciences,
University of Ghana, Legon, Accra, Ghana
2Directorate of Medicine, Endocrine and Diabetes Unit, Komfo Anokye Teaching Hospital, Kumasi, Ghana
Correspondence should be addressed to Ernest Yorke; pavlovium@yahoo.com
Received 29 May 2017; Revised 4 July 2017; Accepted 11 July 2017; Published 27 July 2017
Academic Editor: Franco Veglio
Copyright © 2017 Ernest Yorke et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cushing’s syndrome is a rare entity, and a high index of suspicion is needed for screening in a primary care setting. The clinical
awareness of the primary care physician (PCP) to the highly indicative signs and symptoms such as facial plethora, proximal
myopathy, reddish purple striae, and easy bruisability should alert him to look for biochemical evidence of Cushing’s syndrome
through any of the first-line screening tests, namely, 24-hour urinary free cortisol, overnight dexamethasone suppression test, or
late-night salivary cortisol. Commonly used random cortisol measurements are unreliable; hence, general practitioners are
encouraged to understand the use of these more reliable tests with increased sensitivity and specificity for screening Cushing’s
syndrome. In this write-up, we set out to increase awareness about the presentation of Cushing’s syndrome and current
recommended screening methods as well as their strengths and weaknesses. We relied mainly on the recommendations by the
Endocrine Society Guidelines.
1. Introduction 0.2–5 per million/year and a prevalence of 39–79 per million
in various populations [5]. The average age-of-onset is
Cushing’s syndrome (CS) describes the sign and symptom 41.4 years with a female to male ratio of 3 : 1. Increased prev-
complex due as a result of prolonged supraphysiological alence is seen in those with uncontrolled T2DM, hyperten-
levels of circulating glucocorticoid of any type [1]. CS can sion, or early-onset osteoporosis [5]. Extrapolated estimates
be exogenous (iatrogenic) or endogenous [1]. Worldwide, suggest an incidence of about 20 per million population in
exogenous CS represents the bulk of CS which are due as a Africa [6].
result of medically prescribed glucocorticoids as well as
steroid-containing skin bleaching creams especially in Africa
[2–4]. Endogenous CS is diagnosed when there is increased 3. Clinical Presentation
adrenocorticotropic hormone (ACTH) from a pituitary ade-
noma (Cushing’s disease) or an ectopic source as well as an Clinical features of CS are multisystemic [7]. The signs
independent adrenal source of cortisol over production [1]. and symptoms of CS such as obesity, hypertension, skin
The discussions from here will focus mainly on changes (plethora, striae, and hirsutism), osteopenia, weak-
endogenous CS. ness, psychological problems including depression,menstrual
abnormalities, glucose intolerance, impotence, dyslipidaemia,
2. Epidemiology and retarded growth in children which are recognized in over
half of the cases of CS are also quite commonly seen in general
In its classic form, CS remains a rare condition associated population, yet CS as an entity is relatively rare [2–8]. More-
with diagnostic and therapeutic challenges as well as excess over, signs and symptoms of CS vary from patient to patient
morbidity and mortality [2]. Globally, it has an incidence of and the presentation can be cyclic [2, 8].
2 International Journal of Endocrinology
In pseudo Cushing’s syndrome (pseudo-CS), there is Table 1: Conditions suggested by the Endocrine Society that may
physiologic hypercortisolism in the absence of true CS present as pseudo Cushing’s syndrome [2].
[1, 2]. Such situations may be found in pregnancy, depres-
sion, alcohol dependence, obesity, poorly controlled diabetes, Physiologic hypercortisolism in the absence of Cushing’s
physical stress, malnutrition, anorexia nervosa, strenuous syndrome
exercise, and hypothalamic amenorrhoea; a broader list is May have Cushing’s syndrome features
presented in Table 1 [1, 2]. The clinical features of pseudo- Pregnancy
CS may overlap with CS and also give false positive test Depression
results, and so clinicians must be aware to this fact during Other psychiatric diseases
screening [1, 2, 9]. The rising worldwide prevalence of obe- Alcohol dependence
sity and clinical features of obesity-related metabolic syn- Glucocorticoid resistance
drome typify such overlaps in clinical features as well as
Morbid obesity
difficulties with biochemical diagnosis [10, 11].
Though diagnosing CS is indeed challenging, especially Uncontrolled diabetes
in mild cases, it is extremely crucial because undiagnosed May not have Cushing’s syndrome features
CS increases morbidity (cardiovascular diseases, infection, Physical stress such as hospitalization, surgery, and pain
poor wound healing, osteoporotic fractures, depression, Malnutrition
and growth retardation) and mortality [8]. CS remains Anorexia nervosa
undiagnosed in significant number of patients with diabetes Vigorous chronic exercise
(2-3%), hypertension (0.5–1%), adrenal incidentalomas
Hypothalamic amenorrhea
(6–9%), and osteoporotic fractures (11%) [2]. The mortality
and quality of life associated with CS decrease but not to CBG excess (serum cortisol increase; not UFC)
the population risk after remission of hypercortisolism [7]. CBG: cortisol-binding globulin; UFC: urinary free cortisol.
The clinical features of CS also regress but may not be
complete after successful treatment [12, 13]. convenient, preferably done without hospitalization, and
Again, the existence of comorbid psychological and should be able to differentiate pseudo-CS from true CS with
psychiatric disorders such as mood disorders and major the least number of false positives and negatives [15]. No sin-
depression with hypercortisolism states may be as high as gle test satisfies all these criteria [2].
60% in some cases [2, 14]. Other conditions include mania,
cognitive impairment, and reduced quality of life [2, 14]. 5.2. Screening. Firstly, rule out iatrogenic CS when there is
Whilst a bidirectional causal relationship has been suggested long-term steroid therapy and assess pretest probability of
in some cases, adequate treatment of the underlying cause of CS based on relatively specific signs [2, 9]. These include
the hypercortisolism may not lead to the complete resolution proximal myopathy, easy bruisability, purple striae (>1 cm),
of these comorbid psychological/psychiatric conditions [14]. facial plethora, and, in children, weight gain with decreasing
It is imperative therefore that these aforementioned associ- growth velocity [2].
ated conditions be sought for and managed appropriately Recommended screening tests and algorithm (Figure 1)
using a multidisciplinary team approach [14]. for diagnosis of CS and the principles on which they are
based are as follows [2, 16]:
4. Indications for Screening
(1) 24-hour urinary free cortisol (UFC): there is
The Endocrine Society Guidelines [2] recommend screening increased cortisol production with urinary excretion.
for CS in patients with the following features:
(2) Late-night salivary cortisol (LNSC): there is loss of
(1) Weight gain and central redistribution of fat diurnal rhythm (not achieving late-night nadir).
(2) Multiple progressive features of CS (3) Dexamethasone suppression tests (DST): there is
loss of feedback inhibition on hypothalamic-
(3) Unusual features for age (osteoporosis and hyperten- pituitary-adrenal (HPA) axis.
sion in young)
Dexamethasone-suppressed corticotrophin releasing
(4) Children with retarded growth (decreasing height hormone (CRH) stimulation (Dex-CRH) test may rarely be
percentile and increasing weight) performed to differentiate pseudo-CS (as in alcoholism,
(5) Adrenal incidentaloma compatible with adenoma. obesity, depression, pregnancy, anorexia nervosa, and
uncontrolled diabetes) from true CS [16]. It is described in
more detail elsewhere.
5. What Are the Recommended Screening Tests? Majority of serum cortisol is bound to corticosteroid-
binding globulin (CBG) and albumin, and only 4% is free
5.1. Ideal Screening Test. An ideal screening test for CS [2]. CBG levels increase in pregnancy and during estrogen
should have high sensitivity without missing mild cases therapy, and serum cortisol measurements are unreliable
[15]. The test should be simple, affordable, and socially until estrogens are stopped for more than 6 weeks [16].
International Journal of Endocrinology 3
Exclude exogenous glucocorticoid in all cases of suspected Cushing’s
syndrome (CS) 
Among patients with signs with high discriminatory value, perform any of the
following tests 
ODST (1 mg)
UFC (24-hour collection) LNSC In obese individuals,
Perform at least 2 tests Perform at least 2 tests consider using LDDST
(2 mg) 
Normal test result: CS unlikely
Any abnormal test: CS likely. Normal test result but with low
Refer endocrinologist pretest probability and worsening
signs and symptoms: repeat test in
6 months 
Figure 1: Screening for Cushing’s syndrome at the primary care level. CS: Cushing’s syndrome; UFC: urinary free cortisol; LNSC: late-night
salivary cortisol; DST: overnight dexamethasone suppression test; LDST: low-dose dexamethasone suppression test.
Salivary and urinary cortisol provides a direct assessment of The diagnostic accuracy can be improved by measuring
serum free cortisol as only free cortisol is filtered into saliva urinary creatinine at the same time. Incomplete collection
and urine [17]. These tests are not affected by conditions that of urine is deemed to have occurred, and urine collection
affect CBG levels. Liquid chromatography with tandem mass must be repeated when creatinine levels are <1.5 g per day
spectrometry (LC-MS/MS) is the most validated method to for men and <1 g per day for women [10].
measure free cortisol in both saliva and urine as immunoas-
says such as radioimmunoassay (RIA) and enzyme-linked 6.2. Late-Night Salivary Cortisol (LNSC). Cortisol secretion is
immunosorbent assay (ELISA) tend to give false-positive pulsatile, with maximum secretion in early morning and
results [9, 18]. minimum at midnight (11 PM–2AM) [20]. Any change in
serum cortisol levels is immediately reflected in saliva [7].
Late-night serum and salivary cortisol rely on the fact that
6. Measurements patients with CS have loss of circadian rhythm with lack of
late-night cortisol nadir [20]. Obtaining saliva sample during
6.1. 24-Hour Urinary Free Cortisol (UFC). UFC was earlier bedtime is easy, noninvasive, and stress free and can be done
considered as the gold standard [16]. UFC has the advantage at home. Collected saliva can be stored in a refrigerator for
of detecting hypercortisolism in situations with altered CBG 7 days and sent by mail to the laboratory at room temper-
levels. However, its sensitivity and specificity are lower than ature [20]. LNSC is not reliable in patients with disturbed
other tests and hence mild CS can be missed [16]. Moreover, sleep, shift work, smoking, chewing tobacco, brisk brushing
it gives false positive and negative results in many conditions of teeth, depression, and critical illness [20]. Late-night sali-
and with many drugs [17]. High fluid intake, incomplete col- vary cortisol greater than 145ng/dl (4 nmol/liter) suggests
lection, contamination, and decreasing GFR (<60ml/min) CS [2]. Because of variability in cortisol secretion, LNSC
can make UFC unreliable [17]. Interestingly, in a study by should be repeated [2].
Ceccato et al. published in 2015 [19], they found out that
UFC alone performed as well as using a paired combination 6.3. Overnight and Low-Dose Dexamethasone Suppression
of either UFC, DST, and LNSC or all three tests combined. Tests (ODST and LDDST). Dexamethasone suppression test
They concluded that among patients with suspected hyper- (DST) assesses loss of feedback inhibition of CRH and ACTH
cortisolism, UFC measured by LC-MS/MS achieves the best secretion [16]. In ODST, which is a screening test for hyper-
diagnostic accuracy [19]. UFC is unacceptable and inconve- cortisolism, 1mg dexamethasone is taken orally at 11 PM.
nient for many patients, and it cannot assess loss of circadian Serum cortisol levels are checked between 8-9AM next
rhythm, which occurs early in CS [17]. UFC should ideally be morning [21]. In children, 0.3mg/m2 surface area of dexa-
repeated because of variability in cortisol excretion. Diagnos- methasone is used [22]. In LDDST, which is a confirmatory
tic criteria for Cushing’s syndrome using UFC are suggested test for hypercortisolism, 0.5mg dexamethasone is taken
by a value greater than the normal range for the assay [2]. every 6 hours for 2 days (starting from 9PM). Serum cortisol
4 International Journal of Endocrinology
is checked at the beginning and at the end. With ODST and It is recommended that when there is high pretest
LDDST, serum cortisol greater than 1.8μg/dl (50 nmol/liter) probability, patients with a normal test result should be
after dexamethasone suppression suggests the diagnosis of referred to the endocrinologist for further assessment [2].
CS [2]. However, when the results are normal but the pretest proba-
Increase in CBG will lead to false positive whereas a bility is low, the tests should be repeated in 6 months if
decrease in CBG will give false-negative tests results [16]. symptoms and signs progress [2, 15].
Exercise and poor sleep after dexamethasone will lead to false Whilst the use of random serum cortisol is high among
positivity [16]. Enzyme inducers, gastrointestinal malabsorp- many general practitioners, using random cortisol or plasma
tion, and rapid transit time decrease the available drug for ACTH to screen for CS is unreliable and therefore not
suppression and may lead to false positive results [16]. recommended [2, 15].
Enzyme inhibitors and mild hypercortisolism cause false-
negative response [15]. Dexamethasone dose may need 8. Further Tests
modification in obese individuals, and it has been suggested
that the false-positivity rate decreases from 8% to 2% with It is recommended that an endocrinologist should choose
2mg dexamethasone rather than 1mg [23]. In a recent any of these second-line tests. Any positive test should be
review by Loriaux in 2017 [10], he suggests that in popu- confirmed with any of the recommended screening tests
lations with a high prevalence of obesity such as the above (i.e., UFC, LNSC, and ODST) or with dexamethasone-
United States of America, the positive predictive value of suppressed corticotrophin releasing hormone (CRH) stim-
the ODST is only 0.4% and therefore discourages its use ulation test [2]. Midnight serum cortisol can also be done
in diagnosing CS. [2]. The latter two tests are described briefly below.
7. Further Comments 8.1. Dexamethasone-CRH (Dex-CRH) Test. This test com-
bines a LDDST and CRH stimulation test to differentiate
Three tests, which can be performed easily in primary care, pseudo-CS from true CS. True CS patients respond to CRH
are UFC, LNSC, and ODST. Whilst the Endocrine Society injection with increases in cortisol level even when pretreated
Guidelines contends that there is no single best test, LNSC with dexamethasone. 0.5mg of dexamethasone is given every
is the current screening test of choice for majority of 6 hours starting from about 12 noon with the administration
cases [8]. At least two first-line tests should be abnormal of CRH 2 hours after the last dose of dexamethasone. Plasma
to diagnose CS [2]. cortisol and ACTH are measured every 15 minutes for one
LNSC has higher sensitivity and specificity when com- hour [29]. A serum cortisol value >38 nmol/l or 1.4μg/dl
pared to UFC, but the prerequisite is that patient should fifteen minutes after CRH administration suggests CS. A
maintain regular diurnal lifestyle and avoid tobacco chewing, pseudo-CS patient does not respond to CRH injection which
smoking, vigorous brushing, and topical oral steroid prepara- is thought to be due to chronic CRH stimulation hence the
tion [2, 8]. Again, several meta-analyses have shown that blunted response [16, 29]. The sensitivity and specificity of
LNSC has comparable efficiency to UFC and LDDST and this test is 90–100% and 67–100%, respectively [29].
they perform well in both outpatient and inpatient settings
[24–26]. Moreover, LNSC can diagnose mild CS in 17.3% 8.2. Midnight Serum Cortisol. Collecting serum sample for
of patients with normal/near-normal UFC [27]. As pseudo- late-night serum cortisol requires admission for 48 hours.
CS patients maintain intact circadian rhythm, LNSC remains After 48 hours or more of inpatient admission, “sleep” blood
true negative in them whereas UFC shows false positivity samples must be taken within 5–10 minutes after waking and
[20]. Also, after pituitary surgery for Cushing’s disease, for “awake” samples, through an indwelling line to avoid false
disease recurrence is picked up early by LNSC than by UFC positive results [30]. “Sleeping” or “awake” midnight serum
[17]. Due to these favorable characteristics, LNSC is currently cortisol of less than 207nmol/l (7.5μg/dl) is a reasonable
preferred over UFC. It must be stated however that LNSC cut-off to exclude the diagnosis of CS [31].
tests are not routinely available at the primary care level.
In practice, tests used in diagnosing CS vary across 9. Screening Tests in Special Circumstances
different countries and geographical areas of the world and
they partly differ from the currently available guidelines Patients with adrenal incidentalomas do not have consis-
[28]. Valassi et al. analyzed the data on the diagnostic tests tently high urinary and salivary cortisol and are therefore
performed in 1341 patients with Cushing’s syndrome (CS) better screened by DST [2, 27]. When CS is suspected
who have been entered into the European Registry on clinically but laboratory results are normal, cyclic-CS
Cushing’s syndrome (ERCUSYN) database between January should be suspected and confirmed by doing UFC or
1, 2000 and January 31, 2016 from 57 centers in 26 European LNSC during symptomatic phase [26] (Table 2). In nor-
countries [28]. They found out that of the first-line tests, UFC mal pregnancy, UFC excretion is normal in the first tri-
test was performed in 78% of patients, DST in 60%, and mester but increases up to 3-fold by term to values seen
LNSC in 25%. This may be partly due to the differences in in women with Cushing’s syndrome [32]. Therefore, dur-
the availability of the different tests in different countries, ing the second or third trimester, only UFC values greater
and therefore there may be the need for harmonization of than 3 times the upper limit of normal should indicate
guidelines [28]. Cushing’s syndrome [2, 32]. Patients with chronic kidney
International Journal of Endocrinology 5
Table 2: Preferred screening tests in special circumstances [2, 9, 15]. brushing of teeth, and irregular sleep patterns. It is recom-
mended to combine more than one investigation based on
Test not
Situations Test preferred the patient’s presentation and medical history. Any abnor-
preferred mal finding can then be combined with a low-dose DST,
Cyclic Cushing’s syndrome [21] UFC or LNSC DST and if that also turns out positive, further screening and
Mild Cushing’s syndrome [21] LNSC or DST UFC referral to an endocrinologist should be done to localize
Pseudo Cushing’s syndrome [21] LNSC or DST UFC the source.
CS patients on antiepileptics [21] UFC or LNSC DST As each investigation has its strengths and weaknesses
Adrenal incidentaloma [21] DST UFC or LNSC in different circumstances and presentations, the clinical
judgment of the clinician is of extreme importance in
Pregnancy [21] UFC DST, LNSC
screening for CS underlining the need for proper awareness
Severe chronic kidney disease [21] DST or LNSC UFC and sensitization of the PCPs to the existence of this rare
Low pretest probability [15] UFC though potentially treatable disorder. Not withstanding
High pretest probability [15] LNSC these recommendations, due to differences in local guide-
UFC: urinary free cortisol; LNSC: late-night salivary cortisol; DST: lines and availability of these tests across geographical
dexamethasone suppression test. regions of the world, the PCP must tailor his/her request
to reflect local reality.
disease should be screened for CS using DST or LNSC as
UFC measurement are unreliable [2].
Abbreviations
10. Further Steps and Localization
ACTH: Adrenocorticotropic hormone
The primary care doctor should promptly refer all positive CBG: Corticosteroid-binding globulin
cases after initial screening tests. CRH: Corticotropin-releasing hormone
Once diagnosis of CS is made, the next step is to CS: Cushing’s syndrome
determine the cause. The localization of the source of hyper- CVD: Cardiovascular disease
cortisolism should ideally be done by an endocrinologist or a Dex-CRH test: Dexamethasone-suppressed CRH
specialist physician with interest in endocrine disorders [2]. stimulation test
Serum ACTH level will be measured to see if the disease DST: Dexamethasone suppression test
is ACTH-independent or ACTH-dependent [5]. If ACTH ELISA: Enzyme-linked immunosorbent assay
level is suppressed, then an adrenal cause is sought by MRI HPA: Hypothalamic-pituitary-adrenal axis
or CT scan of the abdomen. If ACTH level is high, the patient GFR: Glomerular filtration rate
will have additional tests to determine if there is a pituitary LC-MS/MS: Liquid chromatography with tandem
adenoma or ectopic tumor [2, 5]. mass spectrometry
LNSC: Late-night salivary cortisol
11. Limitations RIA: Radioimmunoassays
T2DM: Type 2 diabetes mellitus
It must be recognized that in practice, there is no universally ULN: Upper limit of normal
agreed approach in screening for CS. As stated earlier, analy- UFC: 24-hour urinary free cortisol.
sis of confirmed cases of CS captured in a European registry
revealed varied use of screening tests across the 26 countries
involved [28]. On a worldwide level, access to these variously Conflicts of Interest
suggested screening tests and payment mechanisms available
There is no competing interest involving any of the authors
vary tremendously.
of this manuscript.
12. Conclusion
Authors’ Contributions
Cushing’s syndrome is a rare entity, and in a primary care
setting, a high index of suspicion is needed for screening. Ernest Yorke conceived the study, participated in its design,
The clinical awareness of the primary care physician to the literature search, and collation of all drafts, and drafted
highly indicative signs and symptoms such as facial plethora, the manuscript. Yacoba Atiase, Josephine Akpalu, and
proximal myopathy, reddish purple striae, and easy bruisa- Osei Sarfo-Kantanka contributed to the study design, litera-
bility should alert him to look for biochemical evidence of ture search, and manuscript draft. All authors read and
CS through any of the first-line screening tests, that is, approved the final version of the manuscript.
24-hour UFC, ODST, or late-night salivary cortisol.
Most often in clinical practice, LNSC is preferred
because of its higher sensitivity and specificity compared Acknowledgments
to the others though strict precautions should be followed
prior to sampling such as avoiding smoking, tobacco, brisk This study was funded by the lead author.
6 International Journal of Endocrinology
References applications in endocrinology,” Experimental and Clinical
Endocrinology & Diabetes, vol. 115, no. 09, pp. 559–570, 2007.
[1] M. Boscaro, L. Barzon, F. Fallo, and N. Sonino, “Cushing’s [19] F. Ceccato, M. Barbot, M. Zilio et al., “Screening tests for
syndrome,” Lancet (London, England), vol. 357, no. 9258, Cushing’s syndrome: urinary free cortisol role measured by
pp. 783–791, 2001. LC-MS/MS,” The Journal of Clinical Endocrinology &
[2] L. K. Nieman, B. M. K. Biller, J. W. Findling et al., “The Metabolism, vol. 100, no. 10, pp. 3856–3861, 2015.
diagnosis of Cushing’s syndrome: an endocrine society clinical [20] Q. Zhang, J. Dou, W. Gu, G. Yang, and J. Lu, “Reassessing
practice guideline,” The Journal of Clinical Endocrinology & the reliability of the salivary cortisol assay for the diagnosis
Metabolism, vol. 93, no. 5, pp. 1526–1540, 2008. of Cushing syndrome,” Journal of International Medical
[3] Y. M. Olumide, A. O. Akinkugbe, D. Altraide et al., Research, vol. 41, no. 5, pp. 1387–1394, 2013.
“Complications of chronic use of skin lightening cosmetics,” [21] T. C. Friedman, “An update on the overnight dexamethasone
International Journal of Dermatology, vol. 47, no. 4, suppression test for the diagnosis of Cushing’s syndrome:
pp. 344–353, 2008. limitations in patients with mild and/or episodic hypercortiso-
[4] J. N. Rozen, E. Alseddeeqi, and J. Rivera, “Cosmetic agents lism,” Experimental and Clinical Endocrinology & Diabetes,
causing endocrinopathy in an African immigrant,” Canadian vol. 114, no. 7, pp. 356–360, 2006.
Family Physician, vol. 58, no. 2, pp. 169–171, 2012. [22] P. C. Hindmarsh and C. G. D. Brook, “Single dose dexameth-
[5] A. Lacroix, R. A. Feelders, C. A. Stratakis, and L. K. Nieman, asone suppression test in children: dose relationship to body
“Cushing’s syndrome,” Lancet (London, England), vol. 386, size,” Clinical Endocrinology, vol. 23, no. 1, pp. 67–70, 1985.
no. 9996, pp. 913–927, 2015. [23] M. Sahin, L. Kebapcilar, A. Taslipinar et al., “Comparison of
[6] US Census Bureau IDB, 2004, June 2017, http://www.cure 1 mg and 2 mg overnight dexamethasone suppression tests
research.com/c/cushings_syndrome/stats-country_printer.htm. for the screening of Cushing’s syndrome in obese patients,”
[7] S. T. Sharma, L. K. Nieman, and R. A. Feelders, “Cushing’s Internal Medicine, vol. 48, no. 1, pp. 33–39, 2009.
syndrome: epidemiology and developments in disease man- [24] T. Carroll, H. Raff, and J. Findling, “Late-night salivary cortisol
agement,” Clinical Epidemiology, vol. 7, pp. 281–293, 2015. for the diagnosis of Cushing syndrome: a meta-analysis,”
[8] H. Raff and T. Carroll, “Cushing’s syndrome: from physiolog- Endocrine Practice, vol. 15, no. 4, pp. 335–342, 2009.
ical principles to diagnosis and clinical care,” The Journal of [25] P. Putignano, P. Toja, A. Dubini, F. P. Giraldi, S. M. Corsello,
Physiology, vol. 593, no. 3, pp. 493–506, 2015. and F. Cavagnini, “Midnight salivary cortisol versus urinary
[9] L. K. Nieman, “Cushing’s syndrome: update on signs, free and midnight serum cortisol as screening tests for
symptoms and biochemical screening,” European Journal of Cushing’s syndrome,” The Journal of Clinical Endocrinology
Endocrinology, vol. 173, no. 4, pp. M33–M38, 2015. & Metabolism, vol. 88, no. 9, pp. 4153–4157, 2003.
[10] D. L. Loriaux, “Diagnosis and differential diagnosis of [26] J. D. Carmichael, G. Zada, and W. R. Selman, “Editorial:
Cushing’s syndrome,” New England Journal of Medicine, making the diagnosis of cyclic Cushing’s syndrome: a position
vol. 376, no. 15, pp. 1451–1459, 2017. statement from the topic editors,” Neurosurgical Focus, vol. 38,
[11] A. J. Cameron, J. E. Shaw, and P. Z. Zimmet, “The metabolic no. 2, article E8, 2015.
syndrome: prevalence in worldwide populations,” Endocrinol- [27] P. C. L. Elias, E. Z. Martinez, B. F. C. Barone, L. M. Mermejo,
ogy and Metabolism Clinics of North America, vol. 33, no. 2, M. Castro, and A. C. Moreira, “Late-night salivary cortisol
pp. 351–375, 2004. has a better performance than urinary free cortisol in the
[12] I. Bourdeau, C. Bard, B. Noël et al., “Loss of brain volume in diagnosis of Cushing’s syndrome,” The Journal of Clinical
endogenous Cushing’s syndrome and its reversibility after Endocrinology & Metabolism, vol. 99, no. 6, pp. 2045–2051,
correction of hypercortisolism,” The Journal of Clinical Endo- 2014.
crinology & Metabolism, vol. 87, no. 5, pp. 1949–1954, 2002. [28] E. Valassi, H. Franz, T. Brue et al., “Diagnostic tests for
[13] A. R. Hermus, A. G. Smals, L. M. Swinkels et al., “Bone mineral Cushing’s syndrome differ from published guidelines: data
density and bone turnover before and after surgical cure of from ERCUSYN,” European Journal of Endocrinology,
Cushing’s syndrome,” The Journal of Clinical Endocrinology vol. 176, no. 5, pp. 613–624, 2017.
& Metabolism, vol. 80, no. 10, pp. 2859–2865, 1995. [29] J. A. Yanovski, G. B. Cutler, G. P. Chrousos, and L. K. Nieman,
[14] N. Sonino, F. Fallo, and G. A. Fava, “Psychosomatic aspects “Corticotropin-releasing hormone stimulation following low-
of Cushing’s syndrome,” Reviews in Endocrine & Metabolic dose dexamethasone administration: a new test to distinguish
Disorders, vol. 11, no. 2, pp. 95–104, 2010. Cushing’s syndrome from pseudo-Cushing’s states,” JAMA,
[15] L. Guignat and J. Bertherat, “The diagnosis of Cushing’s vol. 269, no. 17, pp. 2232–2238, 1993.
syndrome: an Endocrine Society Clinical Practice Guideline: [30] J. Newell-Price, P. Trainer, L. Perry, J. Wass, A. Grossman, and
commentary from a European perspective,” European Journal M. Besser, “A single sleeping midnight cortisol has 100%
of Endocrinology, vol. 163, no. 1, pp. 9–13, 2010. sensitivity for the diagnosis of Cushing’s syndrome,” Clinical
[16] V. Bansal, N. E. Asmar, W. R. Selman, and B. M. Arafah, Endocrinology, vol. 43, no. 5, pp. 545–550, 1995.
“Pitfalls in the diagnosis and management of Cushing’s [31] R. Gilbert and E. M. Lim, “The diagnosis of Cushing’s
syndrome,”Neurosurgical Focus, vol. 38, no. 2, article E4, 2015. syndrome: an endocrine society clinical practice guideline,”
[17] H. Raff, R. J. Auchus, J. W. Findling, and L. K. Nieman, “Urine Clinical Biochemist Reviews, vol. 29, no. 3, pp. 103–106, 2008.
free cortisol in the diagnosis of Cushing’s syndrome: is it worth [32] B. R. Carr, C. R. Parker, J. D. Madden, P. C. MacDonald,
doing and, if so, how?” The Journal of Clinical Endocrinology & and J. C. Porter, “Maternal plasma adrenocorticotropin
Metabolism, vol. 100, no. 2, pp. 395–397, 2014. and cortisol relationships throughout human pregnancy,”
[18] M. Vogeser and K. G. Parhofer, “Liquid chromatogra- American Journal of Obstetrics and Gynecology, vol. 139,
phy tandem-mass spectrometry (LC-MS/MS)-technique and no. 4, pp. 416–422, 1981.
MEDIATORS
of
INFLAMMATION
The Scientific Gastroenterology Journal of
World Journal Research and Practice Diabetes Research Disease Markers
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Journal of International Journal of
Immunology Research Endocrinology
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BioMed 
PPAR Research Research International
Hindawi Publishing Corporation Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014
Journal of
Obesity
Evidence-Based 
Journal of Stem Cells Complementary and Journal of
Ophthalmology International Alternative Medicine Oncology
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Parkinson’s 
Disease
 Computational and  
Mathematical Methods Behavioural AIDS Oxidative Medicine and 
in Medicine Neurology Research and Treatment Cellular Longevity
Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation
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