‘Benign’ Adrenal Gland Tumors Might Cause Harm to Millions

Millions of people are at increased risk of type 2 diabetes and high blood pressure and don’t even know it, due to a hidden hormone problem in their bodies.

As many as 1 in 10 people have a non-cancerous tumor on one or both of their adrenal glands that could cause the gland to produce excess amounts of the stress hormone cortisol.

Up to now, doctors have thought that these tumors had little impact on your health.

But a new study out of Britain has found that up to half of people with these adrenal tumors are secreting enough excess cortisol to raise their risk of diabetes and high blood pressure.

Nearly 1.3 million adults in the United Kingdom alone could suffer from this disorder, which is called Mild Autonomous Cortisol Secretion (MACS), the researchers said.

Anyone found with one of these adrenal tumors should be screened to see if their health is at risk, said senior researcher Dr. Wiebke Arlt, director of the University of Birmingham Institute of Metabolism and Systems Research in England.

“People who are found to have an adrenal tumor should undergo assessment for cortisol excess and if they are found to suffer from cortisol overproduction they should be regularly screened for type 2 diabetes and hypertension and receive treatment if appropriate,” Arlt said.

These tumors are usually discovered during imaging scans of the abdomen to treat other illnesses, said Dr. André Lacroix, an endocrinologist at the University of Montreal Hospital Center, who wrote an editorial accompanying the study. Both were published Jan. 4 in the Annals of Internal Medicine.

Adrenal glands primarily produce the hormone adrenaline, but they are also responsible for the production of a number of other hormones, including cortisol, Lacroix said.

Cortisol is called the “fight-or-flight” hormone, and can cause blood sugar levels to rise and blood pressure to surge — usually in response to some perceived bodily threat.

Previous studies had indicated that about 1 in 3 adrenal tumors secrete excess cortisol, and an even lower number caused cortisol levels to rise so high that they affected health, researchers said in background notes.

But this new study of more than 1,300 people with adrenal tumors found that previous estimates were wrong.

About half of these patients had excess cortisol due to their adrenal tumors. Further, more than 15% had levels high enough to impact their health, compared to those with truly benign tumors.

MACS patients were more likely to be diagnosed with high blood pressure, and were as much as twice as likely to be on three or more blood pressure medications.

They also were more likely to have type 2 diabetes, and were twice as likely to require insulin to manage their blood sugar, the study found.

“This study clearly shows that mild cortisol production is more frequent than we thought before, and that the more cortisol you produce, the more likely to you are to have consequences such as diabetes and hypertension,” Lacroix said.

About 70% of people with MACS were women, and most were of postmenopausal age, the researchers said.

“Adrenal tumor-related cortisol excess is an important previously overlooked health issue that particularly affects women after the menopause,” Arlt said.

Lacroix agreed that guidelines should be changed so that people with adrenal tumors are regularly screened.

“Everybody who is found to have an adrenal nodule larger than 1 centimeter needs to be screened to see if they’re producing excess hormone or not,” he said. “That’s very clear.”

A number of medications can reduce cortisol overproduction or block cortisol action, if an adrenal tumor is found to be causing an excess of hormone.

People with severe cortisol excess can even have one of their two adrenal glands removed if necessary, Lacroix said.

“It is quite possible to live completely normally with one adrenal gland,” he said.

More information

The Cleveland Clinic has more about adrenal tumors.

SOURCES: Wiebke Arlt, MD, DSc, director, Institute of Metabolism and Systems Research, University of Birmingham, U.K.; André Lacroix, MD, endocrinologist, University of Montreal Hospital Center; Annals of Internal Medicine, Jan. 4, 2022

From https://consumer.healthday.com/1-4-benign-adrenal-gland-tumors-might-cause-harm-to-millions-2656172346.html

Desmopressin Stimulation Test in a Pregnant Patient with Cushing’s Disease

https://doi.org/10.1016/j.aace.2021.11.005Get rights and content
Under a Creative Commons license
open access

Highlights

Due to the physiologic rise of ACTH during pregnancy, unstimulated ACTH levels may not be an accurate marker to differentiate between adrenal and ACTH-independent Cushing’s syndrome.

The desmopressin stimulation test can be done during pregnancy to investigate the etiology of Cushing’s syndrome.

Non-gadolinium enhanced pituitary imaging may not detect pituitary adenoma, which is the most common cause of Cushing’s disease. Contrast-enhanced pituitary magnetic resonance imaging should be considered in pregnant women with ACTH-dependent Cushing’s syndrome.

Due to increase maternal and fetal morbidities in active Cushing’s syndrome, prompt diagnosis and appropriate treatment are essential. The treatment of choice is transsphenoidal surgery during the second trimester, preferably at a high-volume pituitary center.

There were significantly lower rates of fetal complications in women with active Cushing’s syndrome than a cured disease, including low birth weight.

Abstract

Objective

The hypothalamic-pituitary-adrenal axis stimulation during pregnancy complicates the investigation of Cushing’s syndrome. Our objective is to present a pregnant patient with Cushing syndrome caused by pituitary tumor in which the desmopressin stimulation test helped in the diagnosis and led to appropriate management.

Case report

A 27-year-old woman with 9-week gestation presented with proximal myopathy for 2 months. She had high blood pressure, wide abdominal purplish striae, and proximal myopathy. Her past medical history revealed hypertension and dysglycemia for 1 year. The 8 AM cortisol was 32.4 μg/dL (5-18), late-night salivary cortisol at 11 PM was 0.7 μg/dL (<0.4), and the mean 24-hour urinary free cortisol was 237.6 μg/day (21.0-143.0). The mean ACTH concentrations at 8 AM were 44.0 pg/mL (0-46.0). Non-gadolinium enhanced pituitary magnetic resonance imaging (MRI) reported no obvious lesion. The desmopressin stimulation test showed a 70% increase in ACTH levels from baseline after desmopressin administration. The pituitary MRI with gadolinium showed an 8x8x7-mm pituitary adenoma. Transsphenoidal surgery with tumor removal was done, which showed ACTH-positive tumor cells. After the surgery, the patient carried on the pregnancy uneventfully.

Discussion

During pregnancy, the ACTH level may not be an accurate marker to help in the differential diagnosis of Cushing’s syndrome. Moreover, non-gadolinium pituitary imaging may not detect small pituitary lesions.

Conclusion

In the present Case, the desmopressin stimulation test suggested the diagnosis of Cushing’s disease, which subsequently led to successful treatment. This suggested that the desmopressin test may serve as a useful test to diagnose Cushing’s disease in pregnant individuals.

Keywords

Cushing’s disease
Cushing’s syndrome
desmopressin stimulation test
pregnancy

Introduction

Pregnancy rarely occurs during the course of Cushing’s syndrome (CS).1,2 Given the increase in maternal and fetal morbidities in women with active CS, early diagnosis and treatment of CS are essential.2

The diagnosis of CS using the usual diagnostic tests is challenging due to stimulation of the hypothalamic-pituitary-adrenal axis during pregnancy. The physiologic rise of ACTH from the 7th week of pregnancy also complicates the investigation for the etiology of CS.1 The concern of gadolinium use during pregnancy can affect the sensitivity in detecting small pituitary lesions in ACTH-dependent CS if using non-gadolinium pituitary imaging. Desmopressin is a vasopressin analog selective for V2 receptors. The desmopressin stimulation test has been proposed as a useful procedure for the differential diagnosis of CS.3 Desmopressin stimulates the increase in ACTH and cortisol in patients with CS caused by pituitary tumor or Cushing’s disease (CD) but not in the majority of normal, obese subjects and patients with adrenal CS or ectopic ACTH syndrome.3,4 However, there were limited data on the desmopressin stimulation test during pregnancy.

Here we present the 27-year-old woman with CS in which the desmopressin stimulation test helped in the diagnosis of CD and led to successful treatment.

Case presentation

A 27-year-old woman with 9-week gestation was referred from the orthopedic department to evaluate CS. She presented with proximal myopathy for 2 months. On physical examination, she had Cushingoid appearance, wide purplish striae, bruising, and proximal muscle weakness. Her blood pressure was 160/100 mmHg, and her body mass index was 32.2 kg/m2. Her past medical history revealed that she had hypertension, dyslipidemia, and impaired fasting glucose for 1 year without taking any medication. She also gained 20 kg in the past 2 years. The 8 AM cortisol (chemiluminescent immunometric assay, Immulite/Siemens) was 32.4 μg/dL (normal , 5.0-18.0), late-night salivary cortisol at 11 PM (electrochemiluminescence immunoassay, Roche Cobas) was 0.7 μg/dL (normal, <0.4), and the mean 24-hour urinary free cortisol (UFC) (radioimmunoassay, Immulite/Siemens) was 237.6 μg/day (normal, 21.0-143.0). ACTH concentrations at 8 AM (chemiluminescent immunometric assay, Immulite/Siemens) were 48.4 and 39.6 pg/mL (normal, 0-46.0) (Table 1). At 12 weeks of gestation, non-gadolinium enhanced pituitary magnetic resonance imaging (MRI) reported a mild bulging contour of the right lateral aspect of the pituitary gland without an obvious abnormal lesion (Figure 2A). The desmopressin stimulation test was then carried out at 14 weeks of gestation. Serial blood samples for ACTH and cortisol were obtained basally (at 8 AM) and at 15, 30, 45, and 60 minutes after the intravenous administration of 10 μg of desmopressin. The results were shown in Table 2. Compared with baseline, ACTH levels increased from 34.7 to 58.9 pg/mL (70%) at 15 minutes after desmopressin administration (a ≥35% increase in ACTH levels was considered an indication of CD in non-pregnant individuals)3 (Figure 1). The pituitary MRI with gadolinium revealed an 8x8x7-mm circumscribed lesion with heterogeneous iso- to hyperintensity on T2W in the right inferolateral aspect of the anterior pituitary lobe. The lesion had a delayed enhancement compared to normal pituitary tissue (Figure 2B). Non-contrast MRI adrenal glands showed bilateral normal adrenal glands without mass or nodule. Other abdominal organs were unremarkable. Regarding comorbidities, she had hypertension and gestational diabetes mellitus (GDM). The HbA1c level was 5.7% (39 mmol/mol). Using a two-step strategy, GDM was diagnosed at 12 weeks of gestation. Hypertension and GDM were controlled with 750 mg of methyldopa and 50 units of insulin per day, respectively.

Table 1. Laboratory investigations of the present Case

Variable At 9 weeks of gestation
8 AM cortisol, μg/dL (5.0-18.0) 32.4
Salivary cortisol (11 PM , <0.4 μg/dL) 0.7
UFC (21.0-143.0 μg/day) 183.5 and 291.6
ACTH, pg/mL (8 AM, 0-46.0) 48.4 and 39.6
DHEAS (8 AM, 35.0-430.0 μg/dL) 378.0
PAC (upright position, 8 AM), ng/dL 5.2
PRA (upright position, 8 AM), ng/mL/hr 2.1
Potassium, mmol/L 3.6

UFC, urinary free cortisol; ACTH, adrenocorticotrophic hormone; DHEAS, dehydroepiandrosterone sulphate; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

Figure 2Pituitary imaging of the present Case. (A) A non-gadolinium MRI of the pituitary gland at 12 weeks of gestation showing a mild bulging contour of the right lateral aspect of the pituitary gland without an obvious abnormal lesion (B) An MRI of the pituitary gland with gadolinium at 14 weeks of gestation showing an 8x8x7-mm circumscribed lesion with heterogeneous iso- to hyperintensity on T2W in the right inferolateral aspect of the anterior pituitary lobe. The lesion had a delayed enhancement compared to normal pituitary tissue.

Table 2. Desmopressin stimulation test results performing at 14 weeks of gestation

Time 0 min 15 min 30 min 45 min 60 min
ACTH (pg/mL) 34.7 58.9 57.4 49.9 38.2
Cortisol (μg/dL) 30.6 30.2 29.7 29.6 31.0

ACTH, adrenocorticotrophic hormone

Figure 1. Percentage of ACTH increase after desmopressin administration (time 0 min).

Transsphenoidal surgery with tumor removal was performed at 18 weeks of gestation. Pathological findings showed a 1.3×1.0x0.3 cm of tissue with segments of the pituitary gland and tumor. There were monomorphous round nuclei, stippled chromatin, indistinct nucleoli, and pale eosinophilic cytoplasm cells. These cells were reactive with ACTH and showed loss of reticulin framework, unlike the normal pituitary gland. The next day after the surgery, her 8 AM cortisol was 6.0 μg/dL. Hydrocortisone supplement was started and continued throughout pregnancy. Antihypertensives were discontinued, and the insulin dosages decreased to less than 20 units per day. At 38 weeks of gestation, she gave birth to a 2300-gm male newborn (small for gestational age). Dysglycemia and hypertension resolved after the delivery. One year after the first child’s delivery, the patient had a spontaneous pregnancy without GDM or hypertension. The 8 AM cortisol was 3.9 μg/dL, and hydrocortisone replacement was continued. The patient successfully delivered a term 3300-gm male infant without fetal or maternal complications. Two years after the first transsphenoidal surgery, a 1-μg cosyntropin stimulation test was performed, the basal cortisol was 11.7 μg/dL, and the peak serum cortisol was 23.8 μg/dL. Steroid replacement was withdrawn.

Discussion

Herein we present a 27-year-old woman who was evaluated during her first pregnancy for clinical and laboratory features suggestive of CD. Her morning serum and late-night salivary cortisol concentrations were elevated in addition to non-suppressed ACTH, but a definitive diagnosis was not obtained by a non-gadolinium pituitary MRI. The diagnosis of CD was suggested, however, by the results of a desmopressin stimulation test. The pituitary MRI with gadolinium was proceeded and revealed a pituitary lesion greater than 6 mm.

The prevalence of pregnancy is low due to reduced fertility in CS. To date, there have been less than 300 pregnant patients with CS reported in the literature.2 In pregnancy, the most frequent etiology of CS is adrenal CS (60%), followed by ACTH-producing pituitary adenomas or CD (35%), and very rarely ectopic ACTH (<5%).1 In contrast, CD is the most common cause of CS in non-pregnant people (approximately 70 percent). The clinical diagnosis of CS during pregnancy may be missed due to overlapping features between pregnancy and CS. However, wide purplish cutaneous striae and proximal myopathy are signs with high discrimination index when CS is suspected.5 These signs are not present in normal pregnancy.

In this present Case, CS was diagnosed with apparent clinical features of CS in addition to an elevated UFC and late-night salivary cortisol. The patient denied taking any supplements and her 8 AM cortisol was not suppressed and therefore did not suggest an etiology of exogenous steroid use. Pregnant women without CS may have elevated UFC and late-night salivary cortisol due to increased total and free plasma cortisol from the first trimester until the end of pregnancy.6 This results from an elevated concentration of cortisol transport protein and the increase in placental ACTH and CRH. According to the current guideline, UFC is the recommended test when CS is suspected during pregnancy.5 Since UFC increases during the second trimester, it may not be a reliable marker after the first trimester of pregnancy unless the level is clearly increased (up to 2- to 3-fold the upper limit of normal values).1 Late-night salivary cortisol is also one of the useful tests to diagnose CS during pregnancy because the circadian rhythm of cortisol is preserved in normal pregnancy. Furthermore, it is not influenced by the changes in the binding proteins.7 However, the previous study has shown that late-night salivary cortisol increased progressively throughout pregnancy. When compared with non-pregnant women, median values of late-night salivary cortisol in pregnant women were 1.1, 1.4, and 2.1 times higher in the first, second, and third trimesters respectively. The cutoff values for late-night salivary cortisol on each gestational trimester were: first trimester 0.255 μg/dL, second trimester 0.260 μg/dL, and third trimester 0.285 μg/dL. The respective sensitivities and specificities in each trimester were: first trimester 92 and 100%, second trimester 84 and 98%, and third trimester 80 and 93%.8

Given the non-suppressed ACTH levels after the 7th week of gestation, we were not able to summarize whether the etiology was adrenal CS or ACTH-dependent CS which could be either CD or ectopic ACTH syndrome. In non-pregnant individuals, ACTH suppression usually identifies adrenal CS. However, in pregnancy, ACTH levels were non-suppressed in half of those with adrenal CS due to continued stimulation of maternal hypothalamic-pituitary-adrenal axis by placental CRH.1 Therefore, using the ACTH thresholds in general populations can lead to misdiagnosis when investigating the etiology of CS in pregnant individuals. The hypothalamic-pituitary-adrenal axis response to exogenous glucocorticoids is blunted in pregnant women. Following an overnight dexamethasone administration, pregnant women without CS may have non-suppressed plasma cortisol and UFC.6 In non-pregnant individuals with CS, the high-dose dexamethasone suppression test identify CD with a sensitivity of 82% and a specificity of 50%.4 During pregnancy, the high-dose dexamethasone suppression test failed to identify almost half of the patients with CD.1 Inferior petrosal sinus sampling is usually avoided due to the risk of excessive radiation exposure. Since the non-gadolinium MRI also showed no obvious pituitary lesion in the present Case, in addition to the limitation of the high-dose dexamethasone suppression test and inferior petrosal sinus sampling in pregnancy, we used desmopressin stimulation to help in the investigation of CD since desmopressin can stimulate an ACTH response in a considerable proportion of patients with CD but not in most patients with adrenal CS or ectopic ACTH syndrome.3,4

Desmopressin has been assigned to pregnancy category B by the US Food and Drug Administration (FDA). In the most recent guideline update on the diagnosis and management of CD, the desmopressin stimulation test can be used to differentiate ectopic CS and CD in patients with normal or high ACTH and have no adenoma or equivocal results of pituitary MRI. However, the guideline did not mention the use of this test in pregnant individuals.9 The literature regarding the use of desmopressin stimulation tests in pregnancy is limited. We were able to identify one study in a pregnant patient with active CS, who was surgically confirmed as CD, in which the desmopressin stimulation test was performed at 10 weeks of gestation and after the delivery. Compared with age-matched healthy non-pregnant women, there were different responses of cortisol and ACTH after desmopressin administration in a pregnant patient with active CS.10 The ACTH peaks after the administration of desmopressin were higher in the pregnant patient. CRH stimulation test was also performed in the pregnant patient with CD. Desmopressin stimulated ACTH values during pregnancy and after the delivery were not significantly different, while the CRH stimulated ACTH values were significantly higher when the test was performed after the delivery. The authors did not mention optimal cutoff values for these diagnostic tests.10 In non-pregnant individuals, the ACTH increase of more than 35% at 15 minutes after the desmopressin administration gave the sensitivity of 84% and the specificity of 43% in the diagnosis of CD.3 Another recent study in ACTH-dependent CS showed that the threshold increase in the ACTH level after desmopressin stimulation of 45% identified CD with a sensitivity of 91% and a specificity of 75%.4 Using the non-pregnant cutoff values for the desmopressin stimulation test, the diagnosis of CD was made in our patient who was later surgically confirmed as CD.

Pituitary microadenomas were the cause of CD in almost 90% of non-pregnant individuals.11 In pregnant women with CD, pituitary microadenomas were also reported to be more common than macroadenomas.1,12 Almost 40% of pituitary microadenomas in CD were invisible or poorly visible in non-contrast MRI, in which contrast-enhanced MRI detected them.13 In the Case series from Lindsay et al., the non-contrast MRI could not correctly identify pituitary adenomas in 38% of pregnant patients with available data.1 The same case series reported a pregnant patient having normal pituitary MRI and was later surgically confirmed as having CD from a 3×3 adenoma with positive staining for ACTH. In the present case, a mild bulging contour of the pituitary gland, although without an obvious abnormal lesion, in addition to desmopressin test results, suggested the need for contrast-enhanced pituitary MRI. Gadolinium contrast is FDA pregnancy category C since it is water-soluble and can cross the placenta into the fetus and amniotic fluid.14 However, since a non-gadolinium MRI may not detect pituitary microadenoma even in patients with normal imaging results,1,15 we suggested physicians consider pituitary MRI with gadolinium as initial imaging in pregnant patients with clinical suspicion of CD.

Prompt diagnosis and treatment of CS are essential due to a higher rate of fetal loss in active CS patients without treatment than those who received either medical or surgical treatment. There are significantly lower rates of various fetal complications, including low birth weight, in women with active CS than in cured CS.2 Although medical and surgical treatment were not compared as prognostic factors for complications, experts recommend transsphenoidal surgery in the second trimester as the treatment of choice for CD in pregnancy.1,15 Medical treatment should be the second choice when surgery cannot be carried out or late diagnosis is made.

Conclusion

In the present Case, the results from the desmopressin stimulation test and the pituitary MRI with gadolinium suggested the diagnosis of CD, which subsequently led to successful treatment. This suggested that the desmopressin test may serve as a useful test to diagnose CD even in the context of pregnancy.

Conflicts of Interest

None of the authors have any potential conflicts of interest associated with this research.

References

Funding Statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

The authors would like to thank you all the colleagues in the Division of Endocrinology and Metabolism, Department of Medicine, Faculty of medicine, Chulalongkorn University for all the support.

Dynamic And Invasive Testing in Cushing’s Disease

Abstract

Purpose

Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing’s syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing’s syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing’s disease (CD).

Methods

Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome.

Results

Among CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6–10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78).

Conclusions

CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.

Introduction

Cushing’s syndrome (CS) is a rare and potentially fatal condition due to chronic exposure to cortisol. After excluding exogenous glucococorticoid assumption from any route, the diagnosis is based on clinical suspicion and further confirmed with appropriate testing as suggested by Endocrine Society Guidelines [urinary free cortisol (UFC), late night serum/salivary cortisol and 1 mg dexamethasone suppression test] [1]. Once the diagnosis of endogenous hypercortisolism is confirmed, the measurement of morning ACTH levels allows to discriminate ACTH-dependent from ACTH-independent CS that originates from primary adrenal disorders. Among ACTH-dependent CS, the most common form is caused by an ACTH-secreting pituitary tumor, a condition named Cushing’s disease (CD), accounting for about 80% of all cases, whereas the rest is due to an ectopic source (EAS); even though ACTH levels are usually higher in EAS than in CD, there is a significant overlap between these two conditions, thus further diagnostic procedures are needed [1]. Desmopressin (DDAVP) stimulatory test is helpful in suggesting risk of recurrence in the post-neurosurgical follow-up, but it seems to have a limited diagnostic utility in the differential diagnosis of ACTH-dependent CS due to the expression of vasopressin receptors in both CD and EAS [2]. Conversely, high-dose dexamethasone suppression test (HDDST) and corticotropin-releasing hormone (CRH) test have been widely used for this purpose and represent the mainstay in the differential diagnosis of ACTH-dependent CS forms [3,4,5,6]. Despite their satisfactory accuracy, there is no consensus on how to interpret their results [7]. Previous studies found that the presence of concordant clear-cut response to both HDDST and CRH test is able to exclude the diagnosis of EAS, irrespective of magnetic resonance imaging (MRI) finding [89]. Even though MRI with intravenous gadolinium administration is certainly useful for individuation of the pituitary tumor, it results in little help in about 30% of cases due to tiny dimensions, localization and characteristics of the ACTH-secreting pituitary adenomas [10]. Conversely, radiological studies may sometimes disclose abnormalities with no functional significance, the so-called “pituitary incidentalomas”, that have been found in about 10% of healthy individuals [11], as in up to 38% of patients with EAS [12]. However, it is noteworthy that the finding of a pituitary incidentalomas larger than 6 mm in patients with EAS is usually very rare [13]. The presence of a microadenoma is therefore not enough for hypercortisolism to be labeled as pituitary-dependent and the role of hormonal tests is crucial for a correct diagnosis. When discordant results to dynamic tests and/or when pituitary MRI shows a lesion < 6 mm, bilateral inferior petrosal sinus sampling (BIPSS) is still recommended as the gold-standard procedure to achieve correct differential diagnosis due to its high sensitivity and specificity [7]. However, even BIPSS is not always fully reliable; false negative results are indeed possible in case of anatomical variations of the venous drainage from the cavernous sinuses to the jugular veins or when BIPSS is performed in a low-normal cortisolemic phase, as might happen in cyclic CS or during treatment with cortisol-lowering medications [14]. Furthermore, BIPSS requires hospitalization, is time- and cost-consuming and in few instances might lead to severe complications [1516]. Given the fact that BIPSS is not 100% accurate, has poor reliability to suggest intrapituitary localization/lateralization and has some drawbacks [17], we collected clinical, biochemical and neuroradiological data of a large series of CD patients as well as biochemical and neuroradiological data of a group of EAS patients with the following aims: (i) to describe the responsiveness to dynamic testing (CRH test, DDAVP test and HDDST) and its performance in the differential diagnosis of ACTH-dependent Cushing’s syndrome in possible different scenarios given by MRI finding; (ii) to assess whether the decision of BIPSS execution can affect surgical outcome of patients affected by Cushing’s disease.

Patients and methods

We performed a retrospective analysis on 148 patients (F/M 113/35, mean age 42.4 ± 14.2 years) affected by CD followed at 2 tertiary care centers in Italy between 2000 and 2017 [Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (62 patients); Endocrinology Unit, Department of Medicine-DIMED, University of Padova (86 patients)].

The diagnosis of hypercortisolism was performed on the basis of typical clinical features in the presence of at least two of the following abnormal tests: high 24-h UFC levels, loss of circadian rhythm in plasma/salivary cortisol and lack of cortisol suppression after 1 mg of dexamethasone overnight [1]. The diagnosis of ACTH-dependent hypercortisolism was confirmed in case of detectable baseline ACTH plasma levels (> 20 ng/L) [18]. Pituitary MRI (magnet strength ranging from 1.5 to 3.0 TESLA over the study period) with gadolinium was performed in all patients and reviewed by experienced neuroradiologists. Differential diagnosis of ACTH-dependent hypercortisolism was established through: (i) CRH test (positive response: ACTH and/or cortisol plasma levels increase by more than 50% and/or 20%, respectively) [1218,19,20]; (ii) high-dose dexamethasone suppression test (HDDST) (positive response: serum cortisol levels reduction to a value of < 50% of the basal level) [19]; (iii) DDAVP test (positive response: increase of both ACTH and cortisol greater than 30% and 20%, respectively) [2122].

For CRH and DDAVP tests, all patients were evaluated after an overnight fast; blood samples for ACTH and cortisol measurements were collected − 15, 0, 15, 30, 45, 60, 90 and 120 min after intravenous bolus injection of human CRH 100 µg or DDAVP 10 µg, respectively.

For HDDST, dexamethasone 8 mg was administered orally at 23.00 h and serum cortisol levels were measured between 8.00 and 9.00 a.m. on the next morning.

The decision whether to perform bilateral inferior petrosal sinus sampling (BIPSS) was guided by clinical judgement considering neuroradiological and biochemical findings. After catheter placement, ACTH was measured simultaneously in a blood sample obtained from each petrosal sinus and from a peripheral vein before and 1, 3, 5, and 10 min after the injection of 1 µg/Kg of CRH.

An inferior petrosal sinus to periphery ratio (IPS:P) ≥ 2 at baseline or ≥ 3 after CRH administration was considered as positive response [23]. All patients included in this study underwent transsphenoidal surgery (TSS) performed by neurosurgeons with recognized expertise in the management of pituitary diseases.

The pituitary origin of ACTH secretion was then confirmed by immediate (serum cortisol < 138 nmol/L within 7 days following TSS) and/or sustained biochemical remission [hypoadrenalism (morning serum cortisol < 138 nmol/L or lack of cortisol response to Synacthen stimulation test considering a cut-off of 500 nmol/L) for at least 6 months] after TSS and/or histological examination (defined as positive immunostaining for ACTH on the adenomatous tissue).

Finally, data describing biochemical responses to CRH test, DDAVP test and HDDST and pituitary MRI in a group of 26 patients (14 of which were presented in a previous publication) [9] with histologically confirmed ectopic ACTH syndrome (EAS) were also collected.

Statistical analysis

Data are shown using mean ± standard deviation for normally distributed continuous variables or median and interquartile range (IQR) for non-Gaussian data and proportion for categorical parameters. Categorical data were analyzed using the χ2 test or the Fisher exact test if the expected value was < 5. Continuous parameters with normal distribution were compared using the t test and non-Gaussian data using the non-parametric test of Mann Whitney. The relation between two or more variable was assessed through logistic regression in case of binary dependent variable and linear regression in case of continuous dependent variable. Sensitivity (SE), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) were calculated with 95% confidence intervals (CI) using the exact binomial method. All statistical analyses were performed using SPSS, version 25 (IBM, Cary, NC, USA).

Results

Neuroradiological findings

Patients with CD were divided into three groups on the basis of MRI results; group A included 97 patients (65.5%) with negative imaging (n = 40, 27% of total) or with a pituitary lesion < 6 mm (n = 57 patients, 38.5%); group B those with visible pituitary adenoma sized between 6 and 10 mm (29 subjects, 19.6%), while group C accounted for patients with macroadenoma (22 patients, 14.9%) (Fig. 1).

Fig. 1

figure1

Different groups of patients according to MRI findings

Among patients with EAS, seven had a microadenoma < 6 mm, while pituitary imaging was negative in 19.

Biochemical characteristics at baseline

Demographic, basal and dynamic biochemical characteristics and remission rates of three groups of patients affected by CD are summarised in Table 1.

Table 1 Demographic, basal and dynamic biochemical characteristics and remission rates of three groups of patients

Basal levels of cortisol, ACTH and UFC were evaluated for each group. Because of different assay methods performed during time, we preferred to use relative UFC (UFC/upper normal limit ratio). Patients of Group C showed higher basal ACTH levels compared to patients with negative MRI imaging or microadenomas (Group A + B) [90(54.5–113.5) vs 44.6(33.7–65.6), p < 0.001), without difference between Group A and Group B. No difference in basal cortisol and relative UFC levels was found between groups.

Late night salivary cortisol levels were evaluated in 73 patients (47 of Group A, 13 of Group B and C) without any difference between groups.

Suppression test

Overall, a positive response to HDDST was observed in 91.4% of cases of CD. The rate of responders to HDDST was similar between negative MRI/microadenomas (Group A + B) and macroadenomas (respectively 92.6% vs 83.3%, p = 0.18) and no differences were found in cortisol levels and percentage of cortisol reduction after HDDST among the three different groups of patients (Table 1).

Six out of 26 patients affected by EAS were responsive to HDDST (23.1%). HDDST had a 91% SE, 77% SP, 95% PPV and 62% NPV to diagnose Cushing’s disease (Table 2).

Table 2 Diagnostic performance of positive response to CRH test, HDDST and their combination for the correct identification of Cushing’s disease

Dynamic tests

Overall, CRH test was positive in 89.4% of CD subjects. The response rate was significantly higher in patients with negative MRI/microadenomas (Group A + B) with respect to those with macroadenomas (91.7% vs 75%, p = 0.04), without difference between Group A and Group B. Likewise, negative MRI/microadenomas showed a higher response in terms of ACTH [140.5 (71.9–284.9) vs 82 (26.4–190.9) p = 0.02] and cortisol percentage increase [61.8 (30.7–92.8) vs 36.8 (15.6–63.1), p = 0.03].

As far as DDAVP is concerned, a positive response was recorded in 70.1% of the whole cohort. In this case, unlike CRH test, the response rate was significantly higher in patients with macroadenomas than in those with negative MRI/microadenomas (90% vs 66.3%, p = 0.03). However, no differences between negative MRI/microadenomas and macroadenomas in terms of percentage increase of ACTH and cortisol were found.

Concordance of positive responses between CRH test and HDDST was observed in 81.5% of all patients (82.4% in Group A, 88.4% in Group B and 66.6% of Group C) without any difference between groups. In four cases, a negative response to both tests was recorded; all these patients had a macroadenoma with a minimum diameter of 20 mm.

Concordant positive responses to CRH and DDAVP tests were observed in 62.6% of patients (62.9% in Group A, 56.5% in Group B and 68.4% in Group C, p = NS between groups). In Group A, the concordance rate between CRH and DDAVP was significantly lower than that observed between CRH test and HDDST (62.9% vs 81.5%, p = 0.035). Additionally, six patients (four of Group A, one of Group B and one of Group C) showed a negative response to both tests.

With regards to EAS, one patient had a positive response to CRH test and six patients to HDDST, respectively. Data regarding DDAVP test were available in 22 out of 26 patients: in this subgroup, a false positive response was observed in 11 patients. However, no patient showed a concordant positive response to CRH test and HDDST or to CRH test and DDAVP test. Conversely, two patients responded to both HDDST and DDAVP test. Although it is beyond the aim of this paper, our data confirm previous studies reporting a higher sensitivity of CRH in respect to HDDST and DDAVP test in this setting [24,25,26].

CRH test showed a SE of 89%, SP of 96%, PPV of 99% and NPV of 62% for the diagnosis of CD (Table 2). The combination of the concordant positive responses to CRH test and HDDST performed better than single tests, reaching a 100% SP and PPV irrespective of pituitary MRI.

Considering only the patients with negative imaging or a pituitary lesion < 6 mm, the SE, SP, PPV and NPV of combined positive responses were 82%, 100%, 100% and 62%, respectively (Table 2). On the other hand, combined negative responses in this subgroup of patients showed a SP and PPV of 100% for the diagnosis of EAS.

Similarly, a positive response to both CRH test and DDAVP test reached a SP and PPV of 100% for the diagnosis of CD (Table 3).

Table 3 Diagnostic performance of positive response to DDAVP test or to the combination DDAVP/CRH and DDAVP/HDDST for the correct identification of Cushing’s disease

Bilateral inferior petrosal sinus sampling in CD

BIPSS was performed in 29/97 patients of Group A and 1/29 patient of Group B. In particular, 20 of 29 patients of Group A had a negative MRI. In four out of these patients, CRH and HDDST were discordant (two negative results for each test) and BIPSS confirmed a pituitary origin of CS. In the other 16 cases, a positive response to both tests was observed: in 15 cases BIPSS confirmed the diagnosis of CD, while a central/periphery ratio of 2.91 after CRH administration was recorded in one case. The latter patient underwent TSS and CD was then confirmed by immediate and long-term remission of disease. Notably, no patient of Group A presented a negative response to both CRH test and HDDST, while four patients presented a combined negative response to CRH and DDAVP tests.

In the remaining nine patients of Group A, MRI showed a visible microadenoma < 6 mm and BIPSS confirmed the diagnosis of CD both in concordant (n = 6) and discordant (n = 3) patients.

BIPSS was not consistent with a pituitary origin in a patient of Group B with discordant tests. However, as her pretest probability of having CD was high (she was a young female without any suggestive features of ectopic CS and no lesion at thoracoabdominal computed tomography), also in this case the patient underwent TSS and both short and long-term remission confirmed the diagnosis of CD.

No complications were observed in 29/30 patients after BIPSS. One patient died about 24 h after the procedure because of cardiac rupture. Since autopsy revealed a left ventricular free-wall rupture after asymptomatic acute myocardial infarction and cortisol related myopathy, this event was considered as unlikely related to BIPSS.

Remission rates after surgery and role of BIPSS in CD patients with inconclusive neuroradiological imaging

Overall, surgical remission was achieved in 107/148 (72.3%) patients. No difference between groups was found, also considering all patients with negative MRI or microadenomas (Group A + B) with respect to those with macroadenomas (Group C) (73.8% vs 63.6%, p = 0.31).

Finally, when considering patients of Group A with concordant positive responses to HDDST and CRH test (n = 75), no difference in surgical outcome was found between patients who performed BIPSS and those who did not [respectively, 14/21 (66.6%) vs 38/54 (70.4%), p = 0.78] (Fig. 2).

Fig. 2

figure2

Remission rate in patients of Group A with concordant positive tests

Discussion

Differential diagnosis of ACTH-dependent CS is challenging and to date a single best approach in the diagnostic work-up of these patients does not exist.

Whereas the usefulness of stimulatory and suppression tests is widely accepted, their role to the light of positive MRI (pituitary adenoma < or > 6 mm) or negative findings is still a matter of debate. In the latter case, although BIPSS still represents the gold-standard procedure for differential diagnosis regardless the results of dynamic tests [718], different clinical approaches and opinions are reported in the literature.

In a recent opinion statement by members of the Italian Society of Endocrinology, Italian Society of Neurosurgery and Italian Society of Neuroradiology that summarizes different strategies adopted in the prescription of BIPSS [27], the authors report two studies in which BIPSS did not show any influence on neurosurgical remission rates. In the first one, Bochicchio and coll. retrospectively analyzed data from 668 patients affected by CD and described that in 98 subjects who underwent BIPSS, surgical failure was similar to patients who did not [28]; however, in this cohort CRH and TRH tests but not HDDST, were performed and selection criteria for BIPSS were not clearly reported. In the second one, Jehle and coll. performed a retrospective analysis of 193 patients with ACTH-dependent CS [29]; also in this case, BIPSS did not affect remission rate after TSS as far as recurrence and long-term remission rates. The procedure was reserved to patients with equivocal scan and/or biochemical tests; however, biochemical evaluation consisted of ACTH and UFC levels, while CRH test was not performed and data about HDDST were lacking in all but six patients.

In a subsequent review about the role of BIPSS in CS, Zampetti et al. [30] suggested that, on the basis of authors’ experience, BIPSS should not be performed in patients with positive response to CRH test (defined as increase > 50% in ACTH and > 30% in cortisol), particularly if a consistent suppression to HDDST is present, independently of MRI findings. This opinion was finally remarked by Losa et al. [14] which pointed out CRH test as the main factor in providing indication to BIPSS.

In this area of controversy, we performed a retrospective analysis on 148 patients with CD and 26 patients with EAS aiming to evaluate the role non-invasive tests in the diagnostic work-up, with secondary focus on the need of BIPSS in CD patients with inconclusive neuroradiological examination. In all 148 patients of our cohort, the diagnosis of CD was confirmed by biochemical remission after TSS, histology and/or > 6 months post-surgical hypoadrenalism.

In agreement with previous data, our results confirm that CRH test and HDDST have high accuracy in differential diagnosis of ACTH-dependent CS [8927]. As a whole, a positive response was observed in 89.4% and 91.4% of patients with CD, and in 3.8% and 23.1% of patients with EAS, respectively. More importantly, the combination of concordant positive responses to CRH test and HDDST reaches 100% specificity and PPV, thus allowing the diagnosis of CD irrespective of MRI findings. Otherwise, a single-test approach is not able to reach a specificity of 100%. The same performance is maintained in the subgroup of patients with negative MRI or with a microadenoma < 6 mm. Furthermore, in this subgroup, a negative response to both CRH test and HDDST is sufficient to make the diagnosis of EAS.

Interestingly, in CD patients, the response rate to CRH test, as far as ACTH and cortisol percentage increase, were significantly higher in patients with microadenomas or negative imaging in respect to those with macroadenomas. A similar observation was recently reported in a group of 149 CD patients where macroadenomas tended to show a lower increase of ACTH after CRH compared to microadenomas [9]. As a negative correlation between baseline secretion and ACTH and cortisol responses to CRH in CD patients has been described [31], suggesting in this context a different degree of negative feedback impairment at the pituitary level, the finding of higher baseline ACTH levels in our patients may represent the most likely explanation for this observation.

Accordingly, the highest rate of false negative responses to dynamic tests were observed in patients with macroadenomas, in which a false negative result to both CRH and HDDST was recorded in four cases; nevertheless, in this condition BIPSS is already overlooked due to the low pretest probability of the co-existence of a pituitary macroadenoma and an ectopic CS.

The role of DDAVP test in differential diagnosis of ACTH-dependent CS is still controversial and a high frequency of false positive results in patients with EAS has been reported [2]. However, in a recent work including 167 patients with CD and 27 patients with EAS, the positive response to both CRH and DDAVP test showed a positive predictive value of 100% for CD in patients with negative MRI and negative computed tomography scan [32]. In our study, similarly to CRH test and HDDST, also the combination of positive responses to both CRH and DDAVP tests reaches a specificity and PPV of 100% for the diagnosis of CD. However, DDAVP test presents low sensitivity and specificity, thus resulting in a high prevalence of false negative and false positive results as well as a concordance rate significantly lower than that observed for CRH test and HDDST in patients with negative MRI or with a microadenoma < 6 mm. In addition, in four of these patients we recorded a concordant negative response to CRH and DDAVP tests that might have resulted in misdiagnosis. Therefore, our data indicate that DDAVP test may represent a valid alternative, in particular when discordant results arise from other dynamic tests, but CRH test, HDDST and their combination perform better and reduce the need to perform BIPSS.

On the other hand, it is well recognized that DDAVP may have an important role in the post-surgical follow-up of CD patients, as the persistence or reappearance of a positive response may precede the clinical recurrence of disease [212233,34,35,36,37,38].

In our series, BIPSS confirmed the diagnosis of CD in 28 out of 30 patients who underwent this procedure. Two negative cases included one patient with a pituitary adenoma sized between 6 and 10 mm but discordant CRH test and HDDST and another one with negative imaging and concordant tests. Notably, in the latter case, a borderline central/periphery ratio of 2.91 was recorded. Nevertheless, diagnosis of CD was subsequently proven by remission after neurosurgery, suggesting that BIPSS returned a false negative result in both patients. The proportion of false negative we observed is in line with previous literature data reporting a prevalence of 3–19%, possibly related to anatomical or biochemical variations of disease [141727303940]. Furthermore, BIPSS is burdened by possible complications. In particular, minor adverse events (i.e., groin hematoma, tinnitus, otalgia) have been reported in about 4% of patients, while severe complications (i.e., brainstem infarction, subarachnoid haemorrhage, pulmonary and deep venous thrombosis) are expected in less than 1% of cases [2730]. As reported above, in our series one patient died 24 h after BIPSS due to cardiac rupture, while no complications in the other subjects were recorded. Although our fatal event was unlikely related to the procedure and complications are rare, all these observations point out the need for an accurate selection of patients referred to BIPSS.

Following the results of diagnostic performance analysis, in those patients with concordant positive responses to CRH test and HDDST but inconclusive neuroradiological findings (i.e., negative imaging or pituitary adenoma < 6 mm), the execution of BIPSS did not improve surgical outcome. Then, our data do not support the routine use of BIPSS in this subgroup of CD patients, in whom BIPSS could have been avoided in 22 out of 29 subjects. In this setting, contrarily to what the current guidelines propose [7131819], CRH test and HDDST seems to be sufficient to confirm the diagnosis of CD and to provide indication to pituitary surgery. Similarly, a negative response to both tests pointed toward EAS diagnosis; in this circumstance BIPSS can be avoided too. Indeed, the present study does not propose to remove BIPSS from the diagnostic work-up of ACTH-dependent CS diagnosis, but to restrict its use when really necessary.

Our study has some limitations: first, its retrospective nature, leading in particular to an inhomogeneous selection of patients referred to BIPSS. Second, our data do not allow to draw conclusions about patients with intermediate pituitary lesion between 6 and 10 mm. Although our approach was to avoid BIPSS even in case of discordant results, except in the presence of clinical features suggestive for ectopic CS (rapid onset, hypokalemia, advanced age), these cases can still represent matter of debate.

On the other side, the strength is represented by the comprehensive and punctual biochemical and diagnostic characterization of patients which in our view makes our results very reliable.

In conclusion, our study confirms that CRH test, DDAVP test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In particular, the combination of CRH test and HDDST allows to achieve the best performance in terms of sensitivity and specificity. In patients with negative MRI or with a microadenoma < 6 mm, the presence of concordant positive response to CRH test and HDDST or to CRH test and DDAVP test seems to be sufficient to establish the diagnosis of CD. In this subgroup of patients, BIPSS should be therefore reserved for those cases with discordant tests.

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Funding

This work was supported by AIRC (Associazione Italiana Ricerca Cancro) grant to GM (IG 2017-20594), Italian Ministry of Health grant to GM (PE-2016-02361797) and by Ricerca Corrente Funds from the Italian Ministry of Health.

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Author notes

  1. E. Ferrante and M. Barbot have equally contributed to this work.

Affiliations

  1. Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Via Francesco Sforza, 35, 20122, Milan, ItalyE. Ferrante, A. L. Serban, G. Carosi, E. Sala, R. Indirli, M. Arosio & G. Mantovani
  2. Endocrinology Unit, Department of Medicine DIMED, University of Padova, Padua, ItalyM. Barbot, F. Ceccato, L. Lizzul, A. Daniele, M. Cuman, M. Boscaro & C. Scaroni
  3. Department of Experimental Medicine, Sapienza University of Rome, Rome, ItalyA. L. Serban
  4. Department of Clinical Sciences and Community Health, University of Milan, Milan, ItalyG. Carosi, R. Indirli, M. Arosio & G. Mantovani
  5. Neurosurgery Department, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, ItalyM. Locatelli
  6. Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyM. Locatelli
  7. Department of Neurosciences, University of Padua, Padua, ItalyR. Manara

Corresponding author

Correspondence to G. Mantovani.

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The study was approved by the Ethics Committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (Comitato Etico Milano Area 2, number 651_2019).

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Ferrante, E., Barbot, M., Serban, A.L. et al. Indication to dynamic and invasive testing in Cushing’s disease according to different neuroradiological findings. J Endocrinol Invest (2021). https://doi.org/10.1007/s40618-021-01695-1

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Keywords

  • Cushing’s disease
  • ACTH-dependent Cushing’s syndrome
  • Differential diagnosis
  • Bilateral inferior petrosal sinus sampling

Free cortisol evaluation ‘useful’ after abnormal dexamethasone test

An assessment of free cortisol after a dexamethasone suppression test could add value to the diagnostic workup of hypercortisolism, which can be plagued by false-positive results, according to data from a cross-sectional study.

A 1 mg dexamethasone suppression test (DST) is a standard of care endocrine test for evaluation of adrenal masses and for patients suspected to have endogenous Cushing’s syndrome. Interpretation of a DST is affected by dexamethasone absorption and metabolism; several studies suggest a rate of 6% to 20% of false-positive results because of inadequate dexamethasone concentrations or differences in the proportion of cortisol bound to corticosteroid-binding globulin affecting total cortisol concentrations.

adrenal glands
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“As the prevalence of adrenal adenomas is around 5% to 7% in adults undergoing an abdominal CT scan, it is important to accurately interpret the DST,” Irina Bancos, MD, associate professor in the division of endocrinology at Mayo Clinic in Rochester, Minnesota, told Healio. “False-positive DST results are common, around 15% of cases, and as such, additional or second-line testing is often considered by physicians, including measuring dexamethasone concentrations at the time of the DST, repeating DST or performing DST with a higher dose of dexamethasone. We hypothesized that free cortisol measurements during the DST will be more accurate than total cortisol measurements, especially among those treated with oral contraceptive therapy.”

Diverse cohort analyzed

Bancos and colleagues analyzed data from adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy) and participants undergoing evaluation for hypercortisolism (n = 196; 16 women on oral contraceptives). The researchers assessed levels of post-DST dexamethasone and free cortisol, using mass spectrometry, and total cortisol, via immunoassay. The primary outcome was a reference range for post-DST free cortisol levels and the diagnostic accuracy of post-DST total cortisol level.

Irina Bancos

“A group that presents a particular challenge are women treated with oral estrogen,” Bancos told Healio. “In these cases, total cortisol increases due to estrogen-stimulated cortisol-binding globulin production, potentially leading to false-positive DST results. We intentionally designed our study to include a large reference group of women treated with oral contraceptive therapy allowing us to develop normal ranges of post-DST total and free cortisol, and then apply these cutoffs to the clinical practice.”

Researchers observed adequate dexamethasone concentrations ( 0.1 µg/dL) in 97.6% of healthy volunteers and in 96.3% of patients. Among women volunteers taking oral contraceptives, 25.5% had an abnormal post-DST total cortisol measurement, defined as a cortisol level of at least 1.8 µg/dL.

Among healthy volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not taking oral contraceptives, and 79 ng/dL for women taking oral contraceptives.

Compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol level was 87.3% (95% CI, 81.7-91.7). All false-positive results occurred among patients with a post-DST cortisol level between 1.8 µg/dL and 5 µg/dL, according to researchers.

Oral contraceptive use was the only factor associated with false-positive results (21.1% vs. 4.9%; P = .02).

Findings challenge guidelines

Natalia Genere

“We were surprised by several findings of our study,” Natalia Genere, MD, instructor in medicine in the division of endocrinology, metabolism and lipid research at Washington University School of Medicine in St. Louis, told Healio. “First, we saw that with a standardized patient instruction on DST, we found that optimal dexamethasone concentrations were reached in a higher proportion of patients than previously reported (97%), suggesting that rapid metabolism or poor absorption of dexamethasone may play a lower role in the rate of false positives. Second, we found that measurements of post-DST total cortisol in women taking oral contraceptive therapy accurately excluded [mild autonomous cortisol secretion] in three-quarters of patients, suggesting discontinuation of oral contraceptives, as suggested in prior guidelines, may not be routinely necessary.”

Genere said post-DST free cortisol performed “much better” than total cortisol among women treated with oral estrogen.

Stepwise approach recommended

Based on the findings, the authors suggested a sequential approach to dexamethasone suppression in clinical practice.

“We recommend a stepwise approach to enhance DST interpretation, with the addition of dexamethasone concentration and/or free cortisol in cases of abnormal post-DST total cortisol,” Bancos said. “We found dexamethasone concentrations are particularly helpful when post-DST total cortisol is at least 5 µg/dL and free cortisol is helpful in a patient with optimal dexamethasone concentrations and a post-DST total cortisol between 1.8 µg/dL and 5 µg/dL. We believe that DST with free cortisol is a useful addition to the repertoire of available testing for [mild autonomous cortisol secretion], and that its use reduces need for repetitive assessments and patient burden of care, especially in women treated with oral contraceptive therapy.”

Novel Predictive Model for Adrenal Insufficiency in Dermatological Patients with Topical Corticosteroids Use: A Cross-Sectional Study

Purpose: This study aimed to identify predictive factors and to develop a predictive model for adrenal insufficiency (AI) related to topical corticosteroids use.
Methods: The research was conducted using a cross-sectional design. Adult patients with dermatological conditions who had been prescribed topical steroids for at least 12 months by the dermatology outpatient departments of the Faculty of Medicine, Chiang Mai University from June through October 2020 were included. Data on potential predictors, including baseline characteristics and laboratory investigations, were collected. The diagnoses of AI were based on serum 8AM cortisol and low-dose ACTH stimulation tests. Multivariable logistic regression was used for the derivation of the diagnostic score.
Results: Of the 42 patients, 17 (40.5%) had AI. The statistically significant predictive factors for AI were greater body surface area of corticosteroids use, age < 60 years, and basal serum cortisol < 7 μg/dL. In the final predictive model, duration of treatment was added as a factor based on its clinical significance for AI. The four predictive factors with their assigned scores were: body surface area involvement 10– 30% (20), > 30% (25); age < 60 years old (15); basal serum cortisol of < 7 μg/dL (30); and duration of treatment in years. Risk of AI was categorized into three groups, low, intermediate and high risk, with total scores of < 25, 25– 49 and ≥ 50, respectively. The predictive performance for the model was 0.92 based on area under the curve.
Conclusion: The predictive model for AI in patients using topical corticosteroids provides guidance on the risk of AI to determine which patients should have dynamic ACTH stimulation tests (high risk) and which need only close follow-up (intermediate and low risk). Future validation of the model is warranted.

Keywords: adrenal insufficiency, topical corticosteroids, predictive model, skin diseases

Introduction

Topical corticosteroids are frequently used for inflammatory skin diseases owing to their anti-inflammatory and immunosuppressive effects. Common indications for use include diseases such as psoriasis, eczema, atopic dermatitis, and vitiligo.1 In clinical practice, a variety of delivery vehicles and potencies of topical corticosteroids are used.1 Prolonged and/or inappropriate use of topical corticosteroids can lead to adverse side effects.2 These adverse side effects can be categorized as cutaneous and systemic side effects. The most common cutaneous side effect is skin atrophy. Systemic side effects include hypothalamic-pituitary-adrenal (HPA) axis suppression, glaucoma, hyperglycemia and hypertension.3

One of the most worrisome adverse side effects from the use of topical corticosteroids is adrenal insufficiency (AI) resulting from HPA axis suppression. Topically applied corticosteroids can be absorbed systemically through the skin and can suppress the HPA axis.4–8 This adverse outcome, the inability to increase cortisol production after stress, can lead to adrenal crisis, which is potentially life-threatening. Tests that are normally used to diagnose or exclude AI include serum morning cortisol and the dynamic ACTH stimulation test.9

Secondary AI from percutaneous absorption of topical corticosteroids is less common than with parenteral or oral administration. The cumulative doses and the durations of oral corticosteroid therapy associated with HPA axis suppression have been well documented.10 Data regarding the dose and duration of oral corticosteroids and HPA axis suppression have similarly been well established. A study by Curtis et al reported that the use of oral prednisolone >7.5 mg/day for an extended period (>3 weeks) was linked to this adverse event, and that the incidence increased with duration.10 However, corresponding data for topical corticosteroids has been limited. The degree of risk of HPA axis suppression from topical corticosteroids use is associated with the level of percutaneous absorption which, in turn, depends on numerous factors including the age of the patient (younger patients are more susceptible), body surface area treated, quantity of topical corticosteroids used, potency of the drug, duration of therapy, body region of application, the associated compounds used, eg, urea or salicylic acid, the characteristics of the diseased skin, the degree of impairment of skin integrity, and the coexistence of hepatic and/or renal disease.11–13 One study reported that HPA axis suppression occurs when high potency steroids are administered at a cumulative dose per week of >50 g.2

Presently, there is a lack of data on predictive factors for AI and no predicative model of the relationship between secondary AI resulting from HPA axis suppression and topical corticosteroids use. A simple predictive model which could help preclude and predict the risk of AI which incorporates both demographic and biochemical data could potentially reduce the number of dynamic ACTH stimulation tests performed. This study aimed to identify potential predictive factors and to design an easy-to-use model for predicting the risk of AI following topical corticosteroids use in dermatological patients.

Materials and Methods

This cross-sectional study was conducted with 42 patients who were seen at the dermatology outpatient departments at the Faculty of Medicine, Chiang Mai University Hospital over a 5-month period (June – October 2020). The study protocol was approved by the Faculty of Medicine, Chiang Mai University, Ethical Committee (Ethical number: MED-2563-07037). Recruited participants were adult dermatological patients (≥18 years) who had used topical corticosteroids for at least 12 months. Patients with pituitary or adrenal diseases, pregnant women and patients who had been treated with either systemic corticosteroids or other local corticosteroids were excluded. Those who meet all the inclusion criteria gave their informed consent prior to the study. This study was conducted in accordance with the Declaration of Helsinki.

Adrenal Function Evaluation

Adrenal function was evaluated by serum morning (8 AM) cortisol and the low-dose ACTH stimulation test. Patients were instructed to suspend use of topical corticosteroids for at least 24 hours before serum morning cortisol measurement and ACTH stimulation tests. In those with serum morning cortisol between 3 and 17.9 µg/dL, ACTH stimulation tests were performed on the same day between 9–11AM to either exclude or diagnose AI. Serum cortisol concentrations were measured at 8 AM 0 (basal cortisol) as well as 20 and 40 minutes after 5 µg ACTH was administered intravenously.

Data Collection

Epidemiological data collected included gender, age, blood pressure, underlying dermatologic diseases, other underlying diseases, body surface area involvement, sensitive area involvement, topical corticosteroid potency, amount and duration of topical corticosteroids use, symptoms of AI and the presence of Cushingoid features. Biochemical data included serum cortisol at 8 AM, 0 (basal cortisol) and at 20 and 40 minutes after ACTH intravenous injection, serum creatinine, electrolytes and albumin. Serum cortisol levels were measured by electrochemiluminescence assay (ECLIA) (Elecsys® Cortisol II assay, Roche Diagnostics GmbH, Mannheim, Germany).

Definitions

An 8AM cortisol level of ❤ µg/dL or a peak serum cortisol level of <18 µg/dL at 20 or 40 minutes after an ACTH stimulation test was defined as having AI.14 Sensitive area involvement included the axilla, groin, face and genitalia. Topical corticosteroids are classified by potency based on a skin vasoconstriction assay, and range from ultra-high potency (class I) to low potency (class VII).15 Since some patients had concurrently used more than one class of corticosteroids in one treatment period, the new variable potency·dose·time (summary of corticosteroids potency (I–VII)16 multiplied by total doses (mg) of corticosteroids use and multiplied by duration (months) of corticosteroids use) was created. Symptoms of AI included lethargy, nausea and vomiting, orthostatic hypotension and significant weight loss. Significant weight loss was defined as a loss of 5% of body weight in one month or a loss of 10% over a period of six months.17 Having Cushingoid features was defined as at least one of the excess glucocorticoid features, eg, easy bruising, facial plethora, proximal myopathy, striae, dorsocervical fat pad, facial fullness, obesity, supraclavicular fullness, hirsutism, decreased libido and menstrual abnormalities.

Statistical Analysis

All statistical analyses were performed using Stata 16 (StataCorp, College Station, Texas, USA). Categorical variables are reported as frequency and percentage, while continuous variables are reported as mean ± standard deviation or median and interquartile range (IQR), according to their distribution. For univariable comparison, Fisher’s exact probability test was used for categorical variables, and the independent t-test or the Mann–Whitney U-test was used for continuous variables. p-values less than 0.05 were considered statistically significant.

Multivariable logistic regression was used in the derivation of the prediction model for AI. Predictors with significant p-values in the univariable analysis were included in the multivariable model. We also included age and treatment duration in the model due to the clinical significance of those factors.4,18 The clinical collinearity among the predictors was also evaluated before the selection of the predictors. We generated a weighted score for each predictor by dividing the logit coefficient of the predictor by the lowest coefficient in the model. The discriminative ability of the final multivariable model was assessed using the area under the receiver operating characteristics (ROC) curve. The calibration of the scores was evaluated using the Hosmer-Lemeshow goodness-of-fit test, where a p-value >0.01 was considered a good fit. For clinical applicability, the appropriate cut-off points for the scores were identified based on sensitivity and specificity. We identified one cut-off point with high sensitivity for ruling out AI and another cut-off point with high specificity for ruling in AI. The positive predictive value for each score category with its corresponding confidence interval were presented. A sample size of at least 25 patients with at least 5 patients with AI was estimated to give 80% power at the 5% significance level.4 There was no missing data in this study.

Results

Baseline characteristics and biochemical investigations are shown in Table 1. Forty-two patients with dermatological diseases were included in this study. Of these, 17 patients (40.5%) had AI of whom 5 (29.4%) were female. The mean age of the group was 56.5 ±15.4 years, the mean duration of treatment was 10.1 ± 6 years, and the majority of patients had psoriasis (n = 14, 82.4%). There was no significant difference in sex, age, duration of treatment, potency dose-time, comorbidities, or underlying skin disease between the AI and non-AI groups. The average body surface area of corticosteroids use was significantly higher in patients with AI than in the non-AI group (27.5 ±18.7 m2 and 10.7 ±11.7 m2, p < 0.001, respectively). Basal serum cortisol levels were significantly lower in the AI group (6.52 ± 4.04 µg/dL) than in the non-AI group (10.48 ± 3.45 µg/dL, p 0.003). Although lower serum morning cortisol levels were observed in the AI group, the difference was not statistically significant (5.24 ± 4.65 µg/dL vs 13.39 ± 15.68 µg/dL, p = 0.069). Three patients were identified as having Cushingoid features. All patients with Cushingoid features had AI.

Table 1 Comparison of Clinical Characteristics Between Patients with a History of Topical Corticosteroids Use for at Least 12 Months Who Were Diagnosed with Adrenal Insufficiency and Those without Adrenal Insufficiency (n = 42)

 

Based on the multivariate logistic regression analysis (shown in Table 2), the significant predictive factors for AI in patients who used topical corticosteroids for more than 12 months were body surface area of corticosteroids use of 10–30% and >30% (POR 18.9, p =0.042, and POR 59.2, p = 0.035, respectively), age less than 60 years (POR 13.8, p = 0.04), and basal serum cortisol of <7 µg/dL (POR 131.5, p = 0.003). Only serum basal cortisol was included in the final multivariable model as there was clinical collinearity among serum morning cortisol and basal cortisol as well as 20- and 40-minute cortisol measurements.

Table 2 Multivariable Model for Prediction of Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38)

 

Predictive risk score was created to determine the probability of patients having AI using the aforementioned three significant predictive factors from the multivariable analysis (Table 2). As previous studies have demonstrated that duration of treatment is a strong predictive factor for AI in corticosteroid users,4,18 this factor was also incorporated in the model. The transformed score for body surface area, age and basal serum cortisol had a range of 0 to 30. For treatment duration, the transformed score was based on cumulative years of treatment. The total score was categorized into three groups: low, intermediate, and high risk (Table 3).

Table 3 Accuracy of the Score to Rule in and Rule Out Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38)

 

The cut-off point of ≥50 suggests high risk for developing AI with a sensitivity of 46.2% and a specificity of 100%, a score of <25 suggests a low risk with a sensitivity of 100% and a specificity of 52%, and a score between 25 and 49 indicates an intermediate risk of having AI. The ROC curve for the model assessing predictive performance which included all significant factors had an AuROC of 0.92 (Figure 1). The Hosmer-Lemeshow goodness-of-fit test revealed non-statistically significant results (p = 0.599), indicating that our newly derived scoring system fits the data well.

Figure 1 Model discrimination via receiver operating characteristic curve in patients with a history of topical corticosteroids use for at least 12 months (n = 42).

 

Discussion

The present study proposes an easy-to-use predictive model for AI following topical corticosteroids use in dermatological patients based on demographic and biochemical factors. The accuracy of the model shows an excellent diagnostic accuracy of 92% based on AuROC. Currently, the diagnosis of AI in dermatological patients with topical corticosteroids use involves multiple steps including screening for serum morning cortisol followed by dynamic ACTH stimulation testing. The proposed simple predictive model, which requires only three demographic data items (age, body surface area of corticosteroids use, duration of use) and one biochemical test (serum basal cortisol), could potentially reduce the number of dynamic ACTH stimulation tests performed, resulting in cost- and time-saving for both patients and health-care facilities.

Based on the proposed cut-off points, we suggest screening of individuals at high risk for having AI, including serum morning cortisol and the ACTH stimulation tests to confirm a diagnosis of AI. If there is evidence of AI, the patient should begin to receive treatment for AI to reduce future complications. For those in the low-risk group, only clinical follow-up should be carried out. In the intermediate-risk group, we recommend regular and close biochemical follow-up including serum morning cortisol and clinical follow-up for signs and symptoms of AI. Signs and symptoms that should raise a high index of suspicion for AI include significant weight loss, nausea and/or vomiting, orthostatic hypotension and lethargy. However, this proposed predictive model was studied in adults and cannot simply be generalized and extrapolated to children or infants.

In our study, 40.5% of the patients were determined to have AI. A previous meta-analysis by Broersen et al reported the percentage of patients with AI secondary to all potencies of topical corticosteroids based on a review of 15 studies was 4.7%, 95% CI (1.1–18.5%).19 The higher prevalence of AI in our study could be a result of differences in patients’ baseline characteristics, eg, duration of treatment, corticosteroids potency and body surface area involvement.

In the predictive model, we incorporated both clinical and biochemical factors which are easy to obtain in actual clinical practice. Some of those predictive factors have been previously reported to be linked to AI. Body surface area of corticosteroids use larger than 10% found to be significantly related to AI, especially in patients with a lesion area of over 30%. This finding is consistent with a study by Kerner et al which suggests the extent of surface area to which the corticosteroids are applied may influence absorption of the drug.20 Regarding the age of the patients, our study found that individuals over 60 years old tended to be at high risk of AI following topical corticosteroids therapy. The underlying explanation is that the stratum corneum acts as a rate-limiting barrier to percutaneous absorption as the stratum corneum in younger individuals is thinner than in older people. Diminished effectiveness of topical corticosteroid treatment in older people was demonstrated in a study by Malzfeldt et al.21 Even though serum basal cortisol is not recommended as a standard test to diagnose AI, a prior study reported that it can be considered as an alternative choice to diagnose AI when serum morning cortisol results are not available. In fact, it has been reported that there is no difference in diagnostic accuracy between serum morning cortisol and basal cortisol22 which supports our finding that serum basal cortisol <7 µg/dL is one of the significant factors related to AI.

The final model found no statistically significant relationship between the incidence of AI and the duration of corticosteroids treatment. However, we decided to include this factor in the final model since previous publications have reported that the duration of treatment is a relevant risk factor for developing AI following continuous topical corticosteroids use. The duration of AI events has been reported to vary between 2 weeks to 18 months.4,18 Additionally, a case report of AI demonstrated that 5 years of topical corticosteroids use can cause AI.6 Together, this suggests that patients with a longer duration of topical corticosteroids use are at increased risk of AI, especially those who also have other risk factors. Although both potency and dosage of topical corticosteroids have been reported to be significantly linked to HPA axis suppression, the present study found only a non-significance link. This could be the result of the small sample size as well as of other factors, eg, body surface area involvement and serum cortisol levels, which could have masked the association between potency and dosage of topical corticosteroids with HPA suppression.

To the best of our knowledge, this study is the first to use these novel predictive factors to develop a predictive model for AI in patients using topical corticosteroids. This model has multiple potential implications. First, the model uses clinical and biochemical factors which are obtainable in many institutes. Second, the model’s risk score provides good diagnostic accuracy in terms of both sensitivity and specificity. Finally, each of the predictive factors in the model has an underlying pathophysiological explanation and is not due simply to chance.

There are some limitations in this study. First, the sample size is relatively small, although it does offer sufficient statistical power for each of the predictive factors. Second, further external validation is needed to validate the predictive performance of the model. Third, the cut-off level of serum cortisol after ACTH stimulation test was based on the older generation of ECLIA assay. There was a study proposed that the cut-off for serum cortisol in the newer generation of cortisol assay should be lower (~14–15 µg/dL) than the previous one (18 µg/dL).23 However, this proposed cut-off has not yet been established in the current guideline for AI. In the future, if the newer cut-off for serum cortisol will have been employed in the standard guideline, our predictive model may lead to overdiagnosis of AI.

Conclusions

The proposed predictive model uses both demographic and biochemical factors to determine the risk of AI in dermatological patients following topical corticosteroids use with a high level of diagnostic accuracy. This model has advantages in terms of a reduction in the number of dynamic ACTH stimulation tests needed, thus saving time and resources. Additionally, it can provide guidance to clinical practitioners regarding which patients should be closely followed up for development of AI. Future external validation of this predictive model is warranted.

Acknowledgments

The authors are grateful to Lamar G. Robert, PhD and Chongchit S. Robert, PhD for editing the manuscript.

Disclosure

The authors report no conflict of interest in this work.

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