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Cushing Syndrome in Paediatric Population

Posted on November 4, 2024 by MaryO

Introduction

Cushing’s syndrome (CS) may be defined as a clinical condition characterised by signs and symptoms resulting from excessive and prolonged exposure to glucocorticoids. CS can be differentiated into an exogenous form due to high-dose and prolonged glucocorticoid treatments and an endogenous form caused by excessive cortisol secretion.

In paediatric population, the exogenous CS represents the most frequent type of CS due to the widespread therapeutic use of glucocorticoids (given by systemic or local routes) for pulmonary, renal, haematological, or rheumatological diseases, more rarely due to an unappropriated administration of glucocorticoids by parents (medical child abuse or “Munchausen syndrome by proxy”). Endogenous CS is very rare, with an overall incidence of 1.2-5 per million per year [1‐4], of which 10% of cases occurs in paediatric age [5, 6].

According to the origin of the hypercortisolism, endogenous CS can be also differentiated into an ACTH-dependent form resulting from ACTH-secreting pituitary neuroendocrine tumours (Cushing’s disease, CD) or ACTH-and or corticotropin releasing hormone (CRH) secreting neuroendocrine tumours outside the hypothalamic-pituitary area (ectopic Cushing syndrome, ECS), and an ACTH-independent form of adrenal origin (adrenal Cushing’s syndrome, ACS) (adenoma, carcinoma or bilateral adrenal hyperplasia). Finally, there are some clinical conditions, such as psychiatric disorders, severe obesity, poorly controlled diabetes mellitus, anorexia or intense physical exercise, that are associated with non-physiological hypercortisolism (non-neoplastic hypercortisolism, NNH, formerly known as Pseudo-Cushing’s syndrome) caused by chronic stimuli on hypothalamic-pituitary-adrenal axis.

NNH, particularly when characterized by moderate hypercortisolism, have often several clinical characteristics similar to CS and the first-line tests for screening endogenous hypercortisolism may provide misleading results, making the differential diagnosis very challenging. Besides the clinical history, the duration of symptoms and the first-line tests, second-line dynamic tests can be performed to better discriminate NNH from CS [7‐9]. A recent systematic review and metanalysis provide an overview about the usefulness of the second-line tests to differentiate NNH from CS [10].

Similar to adult population, CD represents the most common form of CS in paediatric age (about 75–80%), while about 15–20% of cases are ascribed to ACS and less than 2% to ectopic origin, although there is a different distribution by age [11, 12]. In fact, CD occurs often in adolescent and pre-adolescent age, while endogenous CS in children younger than 8 years is mainly caused by adrenal tumours [13, 14]. CD in younger children with a relevant family history may be caused by rare genetic causes, since the pituitary adenomas should be the first presentation of MEN1, AIP gene mutations or more rare genetic mutations (as CDKNIB or DICER1 gene) [15].

According to some large epidemiological series studies, adrenocortical tumours present a peak incidence during the first decade, with a median age at diagnosis of 3–4 years [16] and are relatively more frequent in paediatric age than in adulthood. Paediatric adrenocortical tumours are almost always functional, presenting with virilization due to excess androgen secretion alone or in combination with hypercortisolism in about 80% of cases [16]. Adrenal tumours can be isolated or in the context of predisposing genetic syndromes as Li-Fraumeni or Beckwith-Wiedemann syndrome. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare congenital disorder, occurring in late adolescence, mostly (about 95% of cases) associated with the multiple endocrine neoplasia (MEN) syndrome known as Carney complex [13]. Macronodular adrenal hyperplasia is rarely reported in the paediatric population, while another form of bilateral adrenocortical hyperplasia includes the adrenal lesions in McCune-Albright syndrome, which represents the first cause of CS in infants [5, 13, 17, 18]. ECS is extremely rare in childhood, and is associated to neuroendocrine tumours, mostly bronchial, thymic, renal and duodenal or pancreatic carcinoids [5, 13, 19, 20].

Methods

An extensive MEDLINE search was performed in 2023 for the research question by two authors (LC, GP) independently, and discrepancies were resolved by discussion. A literature search was performed from 1970 to 2023. The following search words were included: “Cushing’s Syndrome, Cushing’s disease, children, childhood, diagnosis, endogenous hypercortisolism”. Search terms were linked to the Medical Subject Headings (MeSH) when possible. Keywords and free words were used simultaneously. Additional articles were identified with manual searches and included thorough review of other meta-analyses, review articles, and relevant references.

Clinical presentation of CS in children

The diagnosis of CS is often difficult due to the insidious onset of hypercortisolism, in absence of relevant early signs of the disease, as well as the rarity of the disease in childhood. For these reasons, the time to diagnosis has been reported as a mean of 33 months (95% CI 29–38) and not dissimilar to adult population [21].

In childhood, the most common and earliest sign of CS is weight gain, which becomes pathognomonic when combined with concomitant growth failure. Generally, the discrepancy between height SDS and BMI SDS is suggestive of CS, although short stature (defined as height inferior to -2 SDS) is not always reported [22, 23]. On the other hand, decreased height velocity or growth arrest always occurs in childhood CS, due to the inhibitory action of glucocorticoids on growth plate cartilage, except for subjects presenting a concomitant hyperandrogenism in which growth may be normal or even increased. Some authors have suggested to consider children with height inferior to 0 SDS and BMI over + 1.5 SDS for CS diagnosis, allowing to differentiate from subjects with simple obesity, which often present tall stature [6, 24]. Ultimately, growth arrest could be considered the main red flag sign for paediatricians in suspected CS.

Other common signs reported in childhood and adolescence include swelling of the face (as plethora or moon face), headaches, striae rubrae, acanthosis nigricans, dorsal cervical or supraclavicular fat pads and osteopenia. The main clinical findings in paediatric CS are showed in Table 1.

Table 1

Clinical characteristics of paediatric cushing syndrome (CS)

	Magiakou 1994 [23]			Devoe 1997 [25]	Storr 2011 [26]	Shah 2011 [22]	Lonser 2013 [27]	Guemes 2016 [28]
Number of patients (F/M)	59 (37/22)			42 (25/17)	41 (15/26)	48 (19/29)	200 (106/94)	30 (14/16)
Period of observation	1982–1992			1974–1993	1983–2010	1988–2008	1982–2010	1983–2013
Subtype of CS	Pituitary (50)	Adrenal (6)	Ectopic (3)	Pituitary	Pituitary	Pituitary	Pituitary	Pituitary (16), Adrenal (11), Ectopic (2), Unknown (1)
Mean age at onset (y) or duration of symptoms (m)	11±4 y	9±6 y	10±3 y	NA	NA	23.6 ± 14.2 m	10.6 ± 3.6 y	12 m (6–18)
Mean age at diagnosis (range)	14±4	10±5	11±4	13.1 y (6.5–18)^a	12.3 ± 3.5 y (5.7–17.8)	14.85 ± 2.5 y (9–19)	13.7 ± 3.7 y	8.9 (0.2–15.5)^a
SDS Height at diagnosis (range)	-1.3±1.5	-1.0±1.3	-0.1±0.9	-1.8 (-3.5 to + 0.3)	-1.8 ± 1.3 (-1.2 to -4.2)	NA^b	NA	-0.3 (-3.2 to + 3.0)^c
Signs and symptoms (%)
Weight gain	90			92	98	98	93	76.6
Growth retardation	83			84	100	83	63	36.6
Facial changes				46	100	98	63
Fatigue	44			67	61		48	40
Pubertal lack or delay				60				10
Hirsutism	78			46	59		56	56.6
Acne	47			46	44		47	50
Amenorrhea (primary or secondary	78						49
Virilization	38				76			26.6
Gynecomastia							16
Osteopenia				74
Dorsal cervical fat pad				28			69
Striae rubrae	61			36	49	58	55	26.6
Acanthosis nigricans	12					75	32
Headache				26	51		38
Hypertension	47			63	49	71	36	50
Psychiatric disorders	19			44	59	46	31	43.3
Sleep disturbances								20
Muscle weakness						48
Easy bruising				28		17	25	20
Glucose intolerance or diabetes						25	7

Abbreviation. F: female; M: male; SDS: Standard deviation score; y: years; m: months; NA: not available. ^a median age; ^b 56% of subjects presented short stature; ^c median SDS height

The excess of adrenal androgens is responsible for the appearance of acne, hirsutism and early secondary sexual development (i.e., precocious pubic hair growth) in prepubertal children, while the consequent inhibition of gonadotropins secretion may lead of a lack or delay of pubertal development. However, in adolescence, adrenal hyperandrogenism and hypogonadism may result in menstrual changes (as oligo- or amenorrhea), virilization or gynecomastia. Adrenocortical tumours are often characterised by severe concomitant hyperandrogenism, presenting with hirsutism, acne or virilization.

Additional clinical features reported in paediatric population include depression, behaviour disorders (as anxiety, mood swings, emotional lability) and asthenia, while other typical signs of CS in adulthood as myopathy-related fatigue, easy bruising or hypertension are less common during childhood and adolescence [6, 22, 23, 25‐29].

Considering the extreme rarity of CS and the increasing incidence of obesity in childhood, an extensive screening of the entire paediatric population with obesity is not recommended. It is however important to raise awareness amongst paediatricians to recognize few key features of CS, like facial changes, weight gain with simultaneous growth failure, prepubertal virilisation as menstrual changes or hypogonadism signs in adolescence.

Since the clinical features of NNH are often indistinguishable from neoplastic CS, a good history and examination (as individual growth charts), in addition to specific diagnostic tests, are needed to better rule out any physical or psychological causes of NNH [9].

In identify the different origin of CS based on symptoms, it should be considered that ECS is more commonly associated with catabolic signs (muscle weakness, osteoporotic fractures), little or no weight gain, hypertension and hypokalaemia due to the mineralocorticoid effect of cortisol excess. In fact, very high cortisol levels can cause the saturation of the type-2 11β-Hydroxysteroid Dehydrogenase (11βHSD-2) enzyme, expressed in renal cortex and responsive to convert cortisol into inactive cortisone, leading to spillover of cortisol to the mineralocorticoid receptor. Because of this biochemical mechanism, severe hypercortisolism may be considered as a functional mineralocorticoid excess state causing hypokalaemia, increased renal tubular sodium reabsorption, consequent intravascular volume expansion and hypertension [30‐32]. However, since the clinical spectrum of presentation of ECS may overlap with CD, the differential diagnosis is challenging and requires the combination of dynamic biochemical testing and multimodal imaging, each with its own pitfalls [17, 20, 33].

Diagnostic workup for CS

Once a possible intake of exogenous corticosteroids has been ruled out through a careful medical history, the first step in the diagnostic workup is the identification of endogenous hypercortisolism.

Screening for endogenous hypercortisolism

Endogenous hypercortisolism in the paediatric population is essentially demonstrated with the following tests: 24-h urinary free cortisol (UFC), late-night salivary or serum cortisol and dexamethasone-suppression testing. Because none of these tests has 100% of diagnostic accuracy, as for adulthood, at least two tests are usually needed to confirm endogenous CS [7]. Table 2 shows the statistical features of the three diagnostic tests reported in the paediatric population.

Table 2

Diagnostic tests performed for endogenous hypercortisolism screening in the paediatric population

Author	Population Age (mean)	Subject characteristics (N)	Test	Cut-off	Sensibility	Specificity
Bickler 1994 [54]	15.7 y (pituitary) 8.1 y (adrenal)	Pituitary (10) Adrenal (2)	UFC	> 60 mg/m²	100% (8/8)
Bickler 1994 [54]	15.7 y (pituitary) 8.1 y (adrenal)	Pituitary (10) Adrenal (2)	LDDST	< 50% of basal serum cortisol	91% (10/11)
Devoe 1997 [25]	13.1 y (6.5–18)^a	Pituitary (42)	UFC	> 70 µg/m²	86% (25/29)
Martinelli 1999 [49]	10.2 ± 5 y	Pituitary (5), Adrenal (6), Obese controls (21)	Late-night salivary cortisol	> 7.5 nmol/l	100% (11/11)	95.2% (20/21)
Gafni 2000 [39]	5–17 y	CS patients (14), Healthy controls (53)	UFC	> 72 µg/m²	93% (13/14)	100% (53/53)
Gafni 2000 [39]	5–17 y	CS patients (14), Healthy controls (53)	Late-night salivary cortisol	> 7.5 nmol/l	93% (13/14)	100% (53/53)
Davies 2005 [47]	12.2 y	Pituitary (14)	Late-night serum cortisol	> 50 nmol/l [1.8 µg/dl]	100% (14/14)
Batista 2007 [38]	3–18 y	Pituitary (80), Adrenal (25), Controls (20)	UFC	> 70 µg/m²	88% (92/105) [PPV 98%]	90% (18/20) [NPV 58%]
Batista 2007 [38]	3–18 y	Pituitary (80), Adrenal (25), Controls (20)	Late-night serum cortisol	> 4.4 µg/dl	99% (104/105) [PPV 100%]	100% (20/20) [NPV 95%]
Shah 2011 [22]	14.85 ± 2.5 y	Pituitary (48)	Late-night serum cortisol	> 3.2 µg/dl	100% (38/38)
			LDDST (30 µg/kg/day [max 2 mg/day] divided every 6 h for 48 h	≥ 1.8 µg/dl	100% (48/48)
				≥ 5 µg/dl	94% (45/48)
Storr 2011 [26]	12.3 ± 3.5 y	Pituitary (41)	LDDST (30 µg/kg/day [max 2 mg/day] divided every 6 h for 48 h)	< 50 nmol/l [1.8 µg/dl]	92% (35/38)
Lonser 2013 [27]	13.7 ± 3.7 y	Pituitary (200)	UFC	Age-appropriate reference	99% (177/179)
			UFC	> 70 µg/m²	88% (155/177)
			Late-night serum cortisol	> 7.5 µg/dl	97% (188/193)
Shapiro 2016 [40]	11.7 y (pituitary), 12.9 y (adrenal), 11.5 y (controls)	Pituitary (39), Adrenal (8), Control (19)	UFC (different assays)	Corrected for BSA	89% (34/38)	100%
Wędrychowicz 2019 [55]	11.7 y	Pituitary (4)	UFC	> 55 µg/24 h	100% (4/4)
			Late-night serum cortisol	> 4.4 µg/dl	100% (4/4)
			Overnight DST (1 mg at 11.00 p.m.)	< 1.8 µg/dl	75% (3/4)
Guemes 2016 [28]	8.9 y (0.2–15.5)^a	Pituitary (16), Adrenal (11), Ectopic (2), Unknown (1)	UFC	> 275 nmol [100 µg]/24 h	94% (17/18)
			Late-night serum cortisol	> 138 nmol/l [5 µg/dl]	100% (27/27)
			LDDST (20 µg/kg/day [max 2 mg/day] divided every 6 h for 48 h)	< 50 nmol/l [1.8 µg/dl]	100% (20/20)

Abbreviation. N: number; y: years; UFC: Urinary free cortisol; DST: dexamethasone suppression test; LDDST: low-dose DST; PPV: Positive Predictive Value; NPV: Negative Predictive Value; BSA: body surface area. ^a median age

Recently, some authors have reported the value of hair cortisol measurements as a good marker of hypercortisolism also in paediatric population [34], although further studies are needed to validate this test in the diagnostic workup for CS.

24-h Urinary free cortisol (UFC)

24-h UFC is a long-time used screening test for CS, widely performed in childhood for its non-invasive characteristics and the possibility to collect the 24-h samples at home, although this collection may be difficult for younger subjects. Differently from adults, in paediatric population UFC should be corrected for body surface area, conventionally used to make the normal range homogeneous despite the different cortisol secretion during childhood and puberty [35‐37]. The cut-off of 70 µg/m²/day is associated with an acceptable sensitivity and specificity (over 88% and 90% respectively) [27, 38, 39], even if the normal ranges varied among different paediatric studies, due to assay-specific reference range [25, 28, 40]. In order to reduce intra-patient variability and to provide a better diagnostic accuracy, it is now recognised that at least two UFC measurements should be performed in subjects suspected of CS [27, 38, 40, 41].

Mild forms of hypercortisolism may have a false-negative UFC assay, because free cortisol appears in the urine only when serum cortisol exceeds the plasma protein binding capacity. On the other hand, false-positive elevation of UFC measurements should be caused by NNH, as physical or emotional stress, severe obesity or depression. In fact, obese children and adolescents may present slightly elevated UFC, particularly when the obesity is associated with metabolic syndrome [42, 43].

Considering the extremely low prevalence of CS in the paediatric population, the positive predictive value of UFC measurements is considerably low. For this reason, UFC alone is not recognised as an ideal screening tool, while its use combined with another screening tests is desirable to better detect subjects with endogenous hypercortisolism.

In the last decades, liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays had demonstrated superior sensitivity and specificity compared to traditional immunoassays [44‐46], reducing a considerable analytical bias thanks to its ability to differentiate various glucocorticoid metabolites.

Late night cortisol

Abnormal circadian rhythm of cortisol secretion is a hallmark of CS. The lack of the physiological evening nadir in cortisol secretion is detectable with late-night serum or salivary cortisol tests. As for UFC, at least two late-night cortisol measurements are desirable to improve the diagnostic accuracy, particularly in patients with mild CS.

For serum cortisol measurement, an indwelling intravenous cannula should be placed before sleeping and the blood sample should be taken without waking the child. The assessment of midnight serum cortisol gives the highest sensitivity and specificity for the diagnosis of CS in childhood (99 and 100% respectively using the cut-off of 4.4 µg/dl) [38], despite different normal ranges (between 1.8 and 5 µg/dl) have been considered for paediatric subjects [22, 28, 47].

However, the late-night serum sample requires hospitalization and its use as a screening test for CS is limited.

On the other hand, late-night salivary cortisol measurement represents an easily executable, stress-free test also in outpatient setting. Conventionally, the salivary samples are collected at 11–12 pm, even if some authors suggest to performed it at usual bedtime in order to achieve unstressed levels, resulting from the request to the patient to stay awake beyond the usual bedtime [48]. This precaution, suggested for adult subjects, should be considered also for paediatric population to reduce a potential false-positive rate of the test.

Although the available data in paediatric population are limited, the sensitivity and specificity of late-night salivary cortisol assessment appear to be close to late-night serum cortisol (93–100% and 95–100% respectively) [39, 49].

For all these reasons, late-night salivary cortisol seems to be the best screening test for endogenous hypercortisolism in childhood.

Although the traditional immunoassay methods already have a very high sensitivity, LC-MS/MS assays had demonstrated an improvement of diagnostic specificity and appear to be the most accurate analytical tools also for modern salivary or serum steroid measurements [50‐52]. In fact, the use of LC-MS/MS assay allows the dosage of different cortisol metabolites (as cortisone) in order to better identify the endogenous cortisol production and consequently to reduce false-positive results [8, 51].

Low-dose dexamethasone suppression tests (DST)

In healthy individuals, a supraphysiological exogenous dexamethasone dose inhibits ACTH and consequently cortisol secretion. Therefore, a decrease of serum cortisol concentration below the value of 1.8 µg/dl after 1 or 2 mg dexamethasone dose is considered to be a normal response. The low-dose DST should be performed through two different forms: the 1 mg “overnight” (or Nugent) and the two-day 2 mg (or low-dose Liddle) test.

The “overnight” DST is performed with the administration of 1 mg (or 25 µg/kg in children with body weight < 40 kg) of dexamethasone at 11 PM to 12 AM (midnight), measuring serum cortisol at 8 AM the next morning. In order to ensure a proper DST in adult population, Ceccato et al. propose to measure also dexamethasone after 1 mg-DST with LC-MS/MS assay [53]. At present, no similar data are available among paediatric population, although dexamethasone measurement should be suggested also in children and adolescents to reduce false-positive results due to inadequate bioavailability or incorrect administration of dexamethasone.

The “low-dose Liddle” DST (LDDST) consists of the administration of 2 mg/day of dexamethasone (or 20–30 µg/kg/day in children < 30 kg), divided in 0.5 mg doses every six hours for 48 h, and measurement of serum cortisol within six hours after the last dose.

For both DST, the lack of the physiological serum cortisol suppression (< 1.8 µg/dL) is suspicious for CS. LDDST has demonstrated a good sensitivity (over 90%) for CS in paediatric patients [26, 28], whereas less data regarding the overnight DST sensitivity and specificity are available in childhood [54, 55].

For its ease analysis in an out-patient setting, LDDST is therefore a useful screening test for paediatric patients suspected of CS.

Recently, some authors have investigated the utility of salivary cortisone measurement after DST, that is characterized by a more linear relationship with serum cortisol than salivary cortisol [56]. Moreover, a prospective use of salivary cortisol/cortisone after DST in childhood should be encouraged for its non-invasive and stress-free peculiarity, avoiding venipuncture.

Etiological diagnosis of endogenous CS

Basal electrolytes and ACTH

Levels of serum electrolytes are usually normal, but potassium may be decreased, especially in children with ECS [57]. In children with CD, morning plasma ACTH is commonly detectable (> 5 pg/ml) while those with ACS showed suppressed ACTH [29]. Batista et al. showed that a cut-off of morning ACTH of 29 pg/ml had a sensitivity of 70% and specificity of 100% to differentiate ACTH-dependent from ACTH-independent CS [38]. ACTH concentrations are usually very high in patients with ECS but may be normal in patients with pituitary adenomas [17, 29, 57]. CD should be suspected in patients with biologically moderate signs, without hypokalaemia or marked plasma ACTH elevation and with progressive onset [17, 20, 33].

CRH stimulation test

The CRH test has been suggested as the best non-invasive tool for diagnosing CD. Sensitivity and specificity are reported to be around 80 and 92% (according to study in adults) [17, 58‐60]. This test consists in the intravenous injection of 1 µg/kg CRH (maximum dose 100 µg) [29]. The criterion for diagnosis of CD is a mean increase of 20% above baseline for cortisol value at 15 and 30 min and an increase in the mean ACTH concentration of at least 35% over basal value at 15 and 30 min after CRH administration [17, 29]. Some authors reported the use of ovine CRH (the only available form in the United States, until the mid-2020) in paediatric population [38, 61] as alternative to human CRH. Although it has been described as the ovine CRH can induce a stronger, more prolonged increase in ACTH and, particularly, cortisol compared with human CRH in adult subjects [62], no data are available comparing ovine and human CRH in paediatric population.

Despite children with CD seem to have a more evident cortisol response than adults, making this test more useful in the paediatric age than in adults [17, 26, 29, 63], the recent synthetic human CRH shortage [64] will make CRH test less feasible in favour of other dynamic tests as Desmopressin test [65].

Desmopressin test

Desmopressin is a preferential vasopressin receptor V2 and V3 agonist. Because of the overexpression of the V3 in human ACTH-secreting adenomas, the administration of desmopressin causes a significant rise in ACTH and cortisol levels in most patients with CD [17, 58]. This makes desmopressin administration a suitable test enabling the distinction between neoplastic from NNH [9, 10, 26]. Like CRH test, Desmopressin test results effective, well-tolerated, less expensive, and relatively non-invasive. While the sensitivity is comparable to CRH test, the specificity seems to be lower [17, 58, 60, 66]. Like the other tests, it is probabilistic: the more significant the elevation of ACTH and cortisol, the more probable the diagnosis of corticotropic adenoma [17, 58]. Different cut-off criteria were used to define a positive response. Malerbi et al. showed that the administration of Desmopressin 5–10 µg intravenous determines a cortisol increase above baseline ranging from 61 to 379% in patients with pituitary disease [67]. Sakai et al. using a high percent ACTH rise threshold of 120% reported a positive ACTH response in all 10 patients with CD, whereas all 3 patients with ECS were unresponsive to desmopressin [68]. Tsagarakis et al. showed that desmopressin test (10 µg intravenous) can produce a significant overlap of responses between CD and patients with ECS and therefore it is of limited value in the differential diagnosis of ACTH-dependent CS. This is probably due to the expression of the V2 receptors in tumours with ECS [69]. Desmopressin (10 µg intravenous) in combination with CRH may provide an improvement over the standard CRH test in the differential diagnosis of ACTH-dependent CS [70]. However, the benefit of a desmopressin-CRH combined test results limited [66]. It should be considered that all the above studies included adults [67‐69].

Desmopressin test proved to be effective in increasing the sensibility of Bilateral Petrosal Sinus Sampling (BIPSS) [71]. In a retrospective study including 16 children with CD, Chen et al. showed an increase of the sensitivity of BIPSS from 64.7% at baseline to 83.3% after desmopressin stimulation [72]. Many CD patients respond aberrantly to the desmopressin test. Loss of the desmopressin response, performed in the early post-operative period, is a good predictor for a favourable long-term outcome. Moreover, during follow-up, the return of desmopressin response is predictive of recurrence [66, 71].

Standard high dose dexamethasone suppression test (HDDST)

HDDST or high-dose Liddle test is the oldest described and it is used to differentiate CD from ECS. This test consists in the administration of dexamethasone at a dosage of 80–120µgr/kg/day divided into four doses every 6 h (maximum 2 mg/dose) for 48 h or a single cumulative dose of 80–120µgr/kg (maximum 8 mg) at 11 pm. Plasma cortisol is measured at 8–9 am the morning after the last administration of dexamethasone; the suppression of serum cortisol up to 50% of baseline is suspicious for CD as for adult population [17, 26, 28, 29, 38].

Liu et al. showed that HDDST in combination with pituitary dynamic enhanced MRI (dMRI) had a positive predictive value (98.6%), higher than that of Bilateral Petrosal Sinus Sampling (BIPSS) for the diagnosis of CD [73].

Despite HDDST had reported a good sensibility to identify CD in childhood, this test seems to have a low specificity to exclude ECS because of the high degrees of cortisol suppression after HDDST in children with ECS [19, 28, 29]. In addition, the administration of high-dose dexamethasone in CS patients with high cortisol level can cause severe side effects, including exacerbation of their hypertension and fluctuation of blood glucose. Because of the low accuracy and the risk of severe side effects, this test is less frequently used [29].

Fig. 1

Diagnostic algorithm for screening and differential diagnosis of cushing syndrome in paediatric population

Imaging

Pituitary magnetic resonance imaging (MRI)

Since ACTH-secreting pituitary adenomas are very small (usually < 6 mm in diameter), it is difficult to localize these tumours. Diagnostic workup of CD includes pituitary MRI, but in many patients no tumour is identified. Conventional MRI, even with contrast enhancement, mostly failed to identify ACTH-secreting microadenomas in children with CD. Up to one-third of paediatric and adolescent patients with CD don’t have pituitary tumour detectable at brain MRI. The acquisition protocol should comprise coronal and sagittal spin-echo (SE) slices with gadolinium-enhanced T1 and T2 and millimetric 3D T1 slices [17, 29, 57, 74]. In a retrospective study including 30 children with CD (mean age 12 ± 3 years), Batista et al. showed that pre- and post-contrast spoiled gradient-recalled acquisition in the steady state (SPGR) was superior to conventional pre- and post-contrast T1-weighted SE acquisition MRI in the identification of the microadenomas. In particular, the post-contrast SPGR-MRI identified the location of the tumour in 18 of 28 patients, whereas post-contrast SE-MRI identified the location and accurately estimated the size of the tumour in only 5 of 28 patients (p < 0.001) [74].

Bilateral petrosal sinus sampling (BIPSS)

BIPSS is another powerful diagnostic tool with high sensitivity and specificity, but its invasiveness and high cost limit its wide application, and the indication for BIPSS is still controversial [7, 17, 29, 75, 76]. It consists of the placement of femoral catheters that reach the inferior petrosal sinuses. Successively, blood samples are collected for measurement of ACTH from petrosal sinuses and from peripheral pathway before and after the administration of CRH. Inferior petrosal sinus (IPS) to peripheral (P) ACTH ratio and interpetrosal sinus gradient of one of the two sides to the contralateral side are calculated [75, 76]. In order to avoid incorrect results, it is recommended to verify hypercortisolism with serum cortisol sample immediately before performing BIPSS. Detomas et al. recently described the largest study on BIPSS.

According to the authors, the cut-offs for the ACTH IPS: P ≥ 1.9 at baseline (sensitivity 82.1%, specificity 85.7%) and ≥ 2.1 at 5 min post-CRH (sensitivity 91.3%, specificity 92.9%) allow for the best discrimination between CD and ECS [77]. In a multicentre study including 16 children aged between 4 and 16.5 years, Turan et al. showed that BIPSS is a superior diagnostic work-up than MRI to confirm the diagnosis of CD. Moreover, it showed a significantly higher sensitivity (92.8%) than MRI (53.3%) in detecting adenoma localization at pituitary level, which is crucial for surgical intervention [75]. The use of desmopressin has been reported in alternative to CRH [76]. In a review including case series of children with CS [76], the overall accuracy of BIPSS was 84.1% and became 92.3% after stimulation with desmopressin. The overall lateralizing accuracy of BIPSS was 50%. While BIPSS has a high diagnostic accuracy for the localization to the pituitary gland, it is not reliable for tumour lateralization to the right or left side of the gland. BIPSS is considered the gold standard to reliably exclude ECS and should performed in a specialized centre due to potential patient risk. However, BIPSS is not routinely available in many centres, it may have decreased specificity in children, especially when the pituitary tumour is not lateralized showing misleading results [77, 78]. For these reasons and for the risks related to the invasiveness of the procedure, BIPSS should be reserved only for exceptional cases in children [17, 75, 76].

Radiological anatomic imaging

Subjects with ACS should perform an adrenal Computer Tomography (TC) or MRI to determine the adrenal cause. Despite abdominal TC with contrast-enhanced studies is the cornerstone of imaging of adrenal tumours in adults, MRI scan should be initially preferred in childhood to avoid radiation exposure [79]. Adrenocortical carcinomas are usually unilateral, larger than adenomas, with irregular margins, inhomogeneous contents (with areas of necrosis, haemorrhage and calcification) and avidly enhancement after contrast administration due to their high vascularity [80]. PPNAD is more difficult di identify with radiological studies, because it usually presents normal- or small-sized adrenal glands.

In subjects with suspected ECS, a thin-multislice neck-chest-abdomen-pelvic CT, alone or eventually followed by MRI, should be performed to identify neuroendocrine tumours that generally are very small and difficult to identify [11].

Functional imaging

Second-line functional imaging studies (as Positron Emission Tomography, PET, or scintigraphy) may be useful to provide an accurate etiological diagnosis of CS, particularly when the traditional radiological exams are inconclusive to differentiate CD from ECS. Because of the rarity of ECS, a univocal algorithm regarding the use of new molecular imaging techniques is not well established.

Whereas the ectopic ACTH-secreting tumours express the cell-surface receptors for somatostatin, ¹¹¹In-pentetreotide (OCT) scintigraphy is often chosen as confirmatory exam [81].

The ⁶⁸Gallium-DOTATATE PET/CT scan, using a modified octreotide molecule that also binds to somatostatin receptors, has shown a greater sensitivity for small tumours and may be useful for the tumoral identification in case of negative OCT scan [7]. Finally, ¹⁸FDG-PET/CT seems to be highly sensitive for the detection of aggressive pancreatic lesions [81].

In ACS cases, when adrenocortical carcinoma is suspected and traditional imaging studies (MRI or TC) are not diriment, ¹¹C-metomidate-PET/CT scan allows a non-invasive characterization and staging of the adrenal lesion [82, 83].

Algorithm approach

Clinical history and the age at presentation of symptoms should guide throughout the different diagnosis of endogenous CS. A careful personal history, supported by patient growth charts, physical examination and screening tests should be able to rule out any physical or neuropsychiatric causes of NNH, even if second-line dynamic tests are sometimes needed to distinguish NNH from neoplastic CS.

Although CD is the main cause of CS in children older than 8 years, the clinical presentation of ECS may overlap with CD and the differential diagnosis of CS may be challenging, requiring the combination of dynamic biochemical tests and multimodal imaging.

Since none of the dynamic tests show a perfect sensitivity and specificity, using more than one dynamic test might improve accuracy. A non-invasive approach using a combination of three or four tests, specifically CRH and desmopressin stimulation tests plus MRI, followed by total-body CT, if biochemical and anatomical findings are discordant, correctly diagnose CD in approximately half of patients, potentially eliminating the need for BIPSS [17, 84]. If a pituitary tumour is detected on MRI and dynamic testing results are consistent with CD, BIPSS is not necessary for diagnosis. Since ECS in children is extremely rare, the algorithm approach in children may differ from the adult approach. Findings of ACTH-dependent CS, doubtful CRH test and normal pituitary MRI should be followed by extended imaging (whole-body CT/MRI or functional imaging). Considering the extremely rarity of ECS, the great majority of ACTH-dependent hypercortisolism, even with normal pituitary MRI, corresponds to CD due to a pituitary lesion not yet visible [17]. For this reason, BIPSS should be used only exceptionally in children. A diagnostic algorithm is proposed in Fig. 1.

Conclusions

We provide detailed revision on the diagnostic evaluation of children and adolescents presenting with signs and symptoms suspicious for CS and guidance on the workup from the confirmation of endogenous hypercortisolism to the etiological diagnosis of such a rare challenging condition.

Declarations

Ethical approval

This article does not include research on human participants and/or animals.

Informed consent is not required.

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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From https://www.springermedizin.de/cushing-syndrome-in-paediatric-population-who-and-how-to-screen/50061094

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Atypical Presentation of Cushing’s Disease With Weight Loss and Hypokalemia

Posted on October 29, 2024 by MaryO

Abstract

Summary

ACTH-secreting pituitary adenomas causing Cushing’s disease (CD) typically present with weight gain, whereas weight loss and hypokalemia in endogenous Cushing’s patients are suggestive of ectopic ACTH production. We report a case of CD presenting with atypical features of marked weight loss and hypokalemia. A 75-year-old female was admitted to the hospital with a history of profound weight loss, associated with uncontrolled hypertension, hyperglycemia, severe proximal muscle weakness, and hypokalemia. Subsequent investigations, including 24-h urinary free cortisol, 48-h low-dose dexamethasone suppression test, MRI of the sella, and bilateral inferior petrosal sinus sampling, confirmed CD without any evidence of ectopic ACTH production. She became eucortisolemic with medical therapy of ketoconazole and cabergoline, subsequently regained her weight, and became normokalemic. This case illustrates that patients with CD may present with symptoms and biochemical findings that would otherwise suggest ectopic ACTH production.

Learning points

Patients with CD do not always present with classical clinical features and may present with symptoms and biochemical findings that would otherwise suggest ectopic ACTH production.
While most patients with CD typically lose weight after biochemical remission, some patients gain weight after the normalization of cortisol levels.
This case highlights the need to entertain a broad differential in patients presenting with hypokalemia and weight loss and the need to exclude hypercortisolemia.

Background

Pituitary corticotropin (ACTH)-induced Cushing’s disease (CD) accounts for approximately 70% of patients presenting with Cushing’s syndrome (1). ACTH-producing pituitary adenomas are typically microadenomas and, in over a third of CD patients, there is no demonstrable lesion on MRI (2). Clinical and biochemical diagnosis of CD may be challenging, as patients can present with varied symptoms that overlap with other comorbidities. Progressive weight gain associated with central adiposity is a common manifestation of CD occurring during the early stage of the disease. While nonspecific features such as hypertension, diabetes, cardiac hypertrophy, arterial and venous thrombosis, electrolyte abnormalities, and psychiatric disturbances also occur frequently, the more discriminatory signs of hypercortisolemia include proximal myopathy, facial plethora, easy bruising, and wide striae (2). Weight loss with associated hypokalemia typically suggests an underlying ectopic ACTH production. Here we report an unusual case of pituitary ACTH-induced CD who presented with significant hypokalemia and marked weight loss which resolved with medical control of CD.

Case presentation

A 75-year-old female with a history of type 2 diabetes, hypertension, osteoporosis, and coronary artery disease presented to the emergency department (ED) with profound proximal muscle weakness associated with a serum potassium of 2.4 mmol/L (normal = 3.6–5.2 mmol/L). She also reported a weight loss of 90 lbs over the previous 2 years. In addition, she had uncontrolled hypertension despite taking three anti-hypertensive agents and worsening glycemic control requiring increasing anti-hyperglycemic therapy; her hemoglobin A1c at presentation was 9.3%.

Investigation

During hospitalization, she underwent further investigation for hypokalaemia and resistant hypertension, which showed an elevated 24-h urine free cortisol (24-h UFC) of 1904.4 nmol/d (upper limit of normal: 485.4 nmol/d) and consequently was referred to Endocrinology for further assessment. Repeat outpatient-based investigations after discharge from the hospital confirmed an elevated 24-h UFC of 1578.4 nmol/d, elevated AM serum cortisol of 1749.2 nmol/L (normal: 80–477.3 nmol/L), non-suppressed serum cortisol of 1238.8 nmol/L (normal response: < 50 nmol/L) after a 48-h low dose dexamethasone suppression test, and an elevated serum ACTH at 8.2 pmol/L (normal: 0.5–2.2 pmol/L). MRI of the sella as well as gallium DOTATATE PET-CT did not show any demonstrable lesion (Figs 1A, B and 2A, B). Subsequently, she underwent bilateral inferior petrosal sinus sampling (BIPSS) using 100 µg ovine CRH, which showed a post-CRH central to peripheral ACTH ratio of 3, lateralizing to the right with a ratio of 2.1. Based on these findings, a diagnosis of MRI-negative CD was made.

Treatment

While awaiting surgical opinion, the patient was started on Ketoconazole 200 mg po TID. She was unable to tolerate a larger dose; therefore, cabergoline 1 mg twice a week was added. The options of trans-sphenoidal pituitary surgery and bilateral adrenalectomy were discussed with the patient, which she declined, and decided to continue with medical therapy.

Outcome and follow-up

Medical therapy was adjusted over the next several weeks until 24-h UFC normalized and remained normal during 24 months of follow-up with the most recent being 85 nmol/d. With biochemical remission of CD, her blood pressure normalized, and she required a reduction in the dose of anti-hypertensive and anti-hyperglycaemic therapy. Her serum potassium levels also normalized. She initially regained 15 lbs but called the clinic when, despite taking medical therapy, she once again began losing weight and her serum potassium dropped to 2.7 mmol/L. Repeat serum AM cortisol was significantly elevated at 935.3 nmol/L, as was 24h UFC at 1457.3 nmol/d. Further inquiry revealed that she had been prescribed omeprazole therapy by her family physician for symptoms of reflux. Omeprazole was discontinued due to its potential effect on decreasing the efficacy of ketoconazole therapy, and her cortisol and potassium levels rapidly normalized. Since then, she has regained 50 lbs, being almost back to her baseline weight, and her mobility and strength have improved from being initially bed-bound to now mobilizing independently using a walker. Pre and post therapy values are summarized in Table 1.

Table 1Key investigations at presentation and recent follow-up visit.

Test	Reference range	At presentation	Recent follow-up
Test	Reference range	24-h urine cortisol (nmol/TV)	ULN=486	1908	85
AM cortisol (nmol/L)	133-537	2371	796
Cortisol post-48h low DMS dose (nmol/L)	<1.8	44.9	NA
ACTH (pmol/L)	2.3-10.1	37.5	14
Potassium (mmol/L)	3.6-5.2	2.4	4.5

DMS= dexamethasone suppression; NA = Not Applicable; ULN = upper limit of normal.

Discussion

Here we report an unusual case of CD presenting with features that were initially highly suggestive of ectopic ACTH production with weight loss rather than the usual weight gain. All of the initial symptoms resolved following biochemical control of hypercortisolemia. In our review of the literature, CD associated with weight loss has previously only been reported in association with severe depression, psychosis, eating disorders, or malignancy (3, 4). For instance, a case of familial CD was reported in a child who also had an intercurrent eating disorder (anorexia), which led to weight loss despite CD (3). Weight loss due to ectopic ACTH-induced CD has also been previously reported, where weight loss was thought to be due to the underlying malignancy (4). However, our patient had well-documented pituitary ACTH-induced CD.

Chronic hypercortisolemia is associated with increased abdominal adiposity that is thought to be caused by the downregulation of adenosine monophosphate-activated protein kinase (AMPK), which is responsible for regulating lipid metabolism (5). Furthermore, glucocorticoids also induce a direct orexigenic effect, which leads to weight gain (6). Weight loss in association with hypercortisolemia, on the contrary, can be a presenting feature of ectopic ACTH-producing tumors such as small cell lung cancer. While the underlying mechanism of weight loss is not fully understood, it is thought to be partly due to cAMP/Protein kinase A (PKA) pathway activation, with an increase in PKA activity resulting in altered downstream regulation of cAMP-related lipogenic and lipolytic proteins (6). In addition, high ACTH secretion and the malignant characteristics of the neoplastic process are also thought to play roles in weight loss (7). Our patient had no evidence of ectopic ACTH production.

A previous study (8) comparing the clinical features of CD in older vs younger patients reported that weight gain was more common in younger individuals, whereas older patients typically presented with catabolic changes, likely due to age-related variability in tissue sensitivity to glucocorticoid receptors and intracellular cortisol signaling. The overall rates of central adiposity were 71.1% in older patients compared with 80.0% in younger patients (8).

Another unusual feature was hypokalemia, which is generally associated with ectopic ACTH production. However, up to 10% of CD patients present with low potassium. Hypokalemia is caused by the mineralocorticoid effect of excess cortisol. Supraphysiologic production of cortisol tends to saturate 11β-hydroxysteroid dehydrogenase type II (11β-HSD2) activity in the renal tubule, which is primarily responsible for converting active cortisol into inactive cortisone. This could lead to excess binding of cortisol to mineralocorticoid receptors, resulting in an increase in potassium excretion and thus hypokalemia. While some studies have suggested that ACTH can also lead to lowering 11β-HSD2 activity causing hypokalemia, others have not found any such correlation (9, 10). In our patient, serum potassium normalized after she achieved eucortisolemia with medical therapy.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

Funding

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

Patient consent

Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/relative of the patient.

Author contribution statement

All authors reviewed the results and approved the final version of the manuscript.

Acknowledgements

We thank Dr Brian Moses (Yarmouth Regional Hospital, NS, Canada) and Dr Scott Lee (Valley Regional Hospital, NS, Canada) for their contributions in managing the patient.

References

1↑Pivonello R, De Martino MC, De Leo M, Simeoli C, & Colao A. Cushing’s disease: the burden of illness. Endocrine 2017 56 10–18. (https://doi.org/10.1007/s12020-016-0984-8)
2↑Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, Boguszewski CL, Bronstein MD, Buchfelder M, Carmichael JD, et al.Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes and Endocrinology 2021 9 847–875. (https://doi.org/10.1016/S2213-8587(2100235-7)
3↑Miller AH, & Yeung SCJ. Hypercortisolism manifesting as severe weight loss, hypokalemia, and hyperglycemia in the emergency department. Journal of Emergency Medicine 2016 50 e187–e190. (https://doi.org/10.1016/j.jemermed.2015.06.084)
4↑Cameron FJ, & Warne GL. Familial Cushing’s disease with severe weight loss occurring in late childhood. Journal of Paediatrics and Child Health 1997 33 74–77. (https://doi.org/10.1111/j.1440-1754.1997.tb00996.x)
5↑Kola B, Christ-Crain M, Lolli F, Arnaldi G, Giacchetti G, Boscaro M, Grossman AB, & Korbonits M. Changes in adenosine 5′-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing’s syndrome. Journal of Clinical Endocrinology and Metabolism 2008 93 4969–4973. (https://doi.org/10.1210/jc.2008-1297)
6↑Ferrau F, & Korbonits M. Metabolic comorbidities in Cushing’s syndrome. European Journal of Endocrinology 2015 173 M133–M157. (https://doi.org/10.1530/EJE-15-0354)
7↑Salgado LR, Fragoso MCBV, Knoepfelmacher M, Machado MC, Domenice S, Pereira MAA, & de Mendonça BB. Ectopic ACTH syndrome: our experience with 25 cases. European Journal of Endocrinology 2006 155 725–733. (https://doi.org/10.1530/eje.1.02278)
8↑Qiao N, Swearingen B, & Tritos NA. Cushing’s disease in older patients: presentation and outcome. Clinical Endocrinology 2018 89 444–453. (https://doi.org/10.1111/cen.13799)
9↑Fan L, Zhuang Y, Wang Y, Liu X, Liu D, Xiang B, He M, Zhang Z, Li Y, Wang Y, et al.Association of hypokalemia with cortisol and ACTH levels in Cushing’s disease. Annals of the New York Academy of Sciences 2020 1463 60–66. (https://doi.org/10.1111/nyas.14205)
10↑Shah NZ, Malik S, Sathyapalan T, & Mohammed K. Refractory hypokalaemia and hypertension with metabolic alkalosis: an acute presentation of Cushing’s disease secondary to a pituitary macroadenoma. BMJ Case Reports 2021 14 e244850. (https://doi.org/10.1136/bcr-2021-244850)
From https://edm.bioscientifica.com/view/journals/edm/2024/3/EDM24-0011.xml

Filed under: Cushing's, symptoms | Tagged: Cushing's, hypokalemia, weight loss | Leave a comment »

“The Healthcare System Did Fail Me Repeatedly”: a Qualitative Study On Experiences Of Healthcare Among Canadian Women With Cushing’s Syndrome

Posted on October 4, 2024 by MaryO

Abstract

Background

As a rare endocrine disorder, Cushing’s Syndrome (Cushing’s) is characterized by numerous symptoms and a non-specific presentation, leading to a delay to diagnosis for patients with this disease. To date, research examining the lived experiences of patients with Cushing’s in healthcare is absent in the literature. This preliminary inquiry into the healthcare experiences of women with Cushing’s aimed to examine the utility of this line of inquiry to support the patient centered care of individuals with Cushing’s.

Methods

Seven women from across Canada with endogenous Cushing’s participated in the study. Semi-structured interviews were conducted examining participants’ healthcare and body-related experiences with Cushing’s. Results pertaining to healthcare experiences were analyzed for the current study using reflexive thematic analysis.

Results

Four themes emerged whereby women with Cushing’s experienced (1) a lack of patient centered care, characterized by provider miscommunication and medical gaslighting; (2) a misunderstanding of their symptoms as related to weight gain; (3) weight stigma in healthcare encounters; and (4) a shift in their quality of care following diagnosis.

Conclusions

The results highlight the importance of patient centered care as well as the negative impact of commonly reported barriers to patient centered care. Cushing’s specific barriers to patient centered care may include weight stigma as well as the rare incidence of Cushing’s. Further research is needed to better understand the healthcare experiences of people with Cushing’s in Canada.

Peer Review reports

Cushing Syndrome (Cushing’s) is a rare disorder caused by an increase in circulating free cortisol [1]. As receptors for glucocorticoids are widespread throughout the body, the effect of this increase in circulating cortisol is prolific [2]. Symptoms include uncontrollable weight gain, dorsocervical fat pad, facial plethora, purple striae, easy bruising, fatigue, proximal myopathy, hypertension, as well as menstrual irregularities and hirsutism among women [1, 3]. While Cushing’s is most often caused by corticosteroids (i.e., exogenous Cushing’s) with a more easily identifiable cause, this research is focused on endogenous Cushing’s, which occurs at an approximate rate of 3.2 cases per million per year globally [4]. Endogenous Cushing’s is divided into two types: adrenocorticotropic hormone (ACTH) dependent and ACTH independent [2]. ACTH dependent Cushing’s comprise approximately 80% of endogenous Cushing’s cases and is caused by ACTH secreting tumours most often on the pituitary (i.e., Cushing’s disease), or an ectopic ACTH secreting tumour found elsewhere in the body [2]. ACTH Independent Cushing’s cases account for the remaining 20% and are most often caused by adrenal cortical adenomas or hyperplasia [5].

The rare rate of occurrence, coupled with the broad symptomology contributes to the challenges with diagnosing Cushing’s, with a delay to diagnosis of two to six years [6, 7]. Although individuals may experience few symptoms its early stages, disease progression that occurs with delayed diagnosis can lead to significant impairment in daily life as well as hypertension, metabolic diseases, and other complications [8]. Given that the incidence of Cushing’s is higher among women compared to men, [9]. as well as the gendered nature of weight and appearance expectations for women in society (i.e., thinness), [10] understanding the impact of this disease on women is an important, but unexplored, direction for women’s health research.

The non-specific presentation and rare occurrence of endogenous Cushing’s is also important to consider in the context of patient centered care, defined as relationship-based care that meets the needs, priorities, and values of patients [11, 12]. Patient centered care focuses on the creation of a positive therapeutic alliance between patient and provider, with shared power and responsibility in decision making [11, 12]. A recent systematic literature review identified that most barriers to patient centered care occur at the provider level, including lack of training, physician burnout, and poor-quality communication [12]. One potential barrier to patient centered care for individuals with Cushing’s is weight stigma (i.e., stereotypes and negative attitudes about people with higher weights), which is prevalent in healthcare, [13, 14] and is associated with consequences for healthcare utilization [15, 16].

Although researchers have documented the clinical presentation of Cushing’s, [7] approaches to working with patients with a possible diagnosis, [1] as well as treatment approaches and outcomes, [17, 18] there is an absence of research on the lived experience of patients with Cushing’s in healthcare. Given the established delay to diagnosis of Cushing’s [6, 7] and the possible impact of weight stigma on patient centered care, we sought to conduct a preliminary inquiry into the patient experience in primary care. Thus, the aim of this study was to examine the healthcare experiences of women with Cushing’s in Canada, as women experience greater incidence of Cushing’s [9] as well as greater appearance-based sociocultural pressures [10].

Methods

Research team background and epistemological underpinnings

We recognize that our identities and positionalities as researchers have a significant impact on the research we conduct [19]. All authors identify as White cisgender women with lived experiences with weight-related issues, and SCJ has lived experience of Cushing’s Disease. SCJ led this research project as part of her degree requirements in a double-major biology and psychology undergraduate program. SN is a weight stigma researcher with a background in qualitative research. JFS conducts research on body image and eating disorder recovery, with a background in qualitative methods. Further, this research was undertaken from a social constructionist epistemological position, recognizing the power of sociocultural discourses related to appearance, weight, and health on the experiences of higher-weight people in society broadly as well as healthcare specifically [20,21,22]. These sociocultural discourses position weight as an accurate indicator of health that is within individual control, with lower body weights considered healthiest (i.e., “normal” weight body mass index) [20,21,22].

Participants

Participants were seven women from across Canada (see Table 1 for demographics). The mean age of the sample was 44.14 (SD = 13.32) and mean self-reported time to Cushing’s diagnosis after first seeking medical care was 2.14 years (SD = 0.58). Six participants experienced Adrenocorticotropic hormone (ACTH) dependent Cushing’s, while one patient experienced ACTH independent adrenal adenoma. Of the six participants with ACTH dependent Cushing’s, five had an ACTH secreting pituitary adenoma and one participant had an ectopic ACTH producing lung carcinoma. All participants self-declared that they exhibited clinically significant 24-hour urine free cortisol levels, which contributed to their diagnosis.

Table 1 Participant demographics and pseudonyms

Full size table

Procedure

This study received research ethics approval from the first and second authors’ institution (#21–0507). Convenience sampling occurred in February 2022 via a shareable recruitment post on five Facebook support groups for Cushing’s Syndrome. Potential participants were directed to reach out to the first author to indicate their interest in the study. Participation was limited to cisgender women over the age of 18 who had been diagnosed with endogenous Cushing’s and received care in the Canadian healthcare system. Nine individuals from one Facebook support group contacted the researcher, two of whom did not receive treatment in Canada. The remaining seven participants were provided with a consent form and demographics survey, which they completed prior to scheduling a semi-structured interview.

Following the completion of informed consent, interviews took place over zoom, in a private location of the participant’s choosing. To obtain a rich understanding of experiences with Cushing’s, we asked a series of questions about participants’: (1) journey to diagnosis, (2) healthcare experience pre- and post-diagnosis, and (3) perception of body and weight pre- and post-diagnosis. Interview questions were open-ended and provided opportunity for participants to describe positive and/or negative experiences. Please see the Appendix for full interview protocol. Interviews lasted approximately one hour with $30 compensation, were recorded, and were transcribed verbatim by the first author. Following transcription, participants had the opportunity to review their transcript and remove any data they were uncomfortable including in the analysis (i.e., member checking). One participant removed a small portion of her transcript, which did not impact the analysis.

Analysis

Following transcription, anonymization, and member checking, the first and second author used a qualitative descriptive approach [23] in the preliminary data analysis stages to become familiar with the data and the experiences of the seven women interviewed. Two main content areas predominated: (1) negative experiences in healthcare and (2) women’s body image as connected to Cushing’s-related changes. Given these divergent content areas, the research team engaged in a two-pronged approach to qualitative data analysis, one for the negative healthcare experiences (reported here) and one for women’s body image.

The data pertaining to negative experiences in healthcare were analysed using reflexive thematic analysis [24, 25]. This method allowed for a rich and flexible understanding of similarities in individual experiences. To generate themes, the first and second authors read the transcripts line-by-line and assigned descriptive codes, which were then reviewed and re-coded at a more interpretive level to create themes in the data, both latent (i.e., underlying) and semantic (i.e., explicitly stated) [24, 25]. Themes were reviewed and approved by all authors. Throughout data collection and analysis, effort was made to discuss reactions to the data and potential biases.

Results

The results of the inductive thematic analysis indicated four overarching themes in the data: (1) lack of patient centered care prior to diagnosis; (2) patient misunderstanding of symptoms; (3) experienced weight stigma; and (4) diagnosis as a golden ticket to treatment and stigma-reduced care. Each of these themes is reviewed below.

Lack of patient-centered care

Lack of patient-centered care prior to diagnosis often took two forms: (1) provider miscommunication, and (2) medical gaslighting. These sub-themes are described below.

Provider miscommunication. In the beginning stages of their investigations, participants reported difficulties in communication with their primary care providers. Honey stated that she was “going back and forth continually, feeling like I wasn’t being heard, feeling like I had to fight for every… For every feeling. I had to try to justify everything I was saying.” Similarly, Abby noted: “I’d started to wake up in the morning with little bruises on my body like almost like a fingerprint. And I thought that was weird and I brought it up to her … And she was like oh that, there’s nothing wrong with that, it’s fine.” Participants described confusion and worry when they perceived that something was wrong but did not perceive they were being taken seriously by their primary care provider.

Sometimes, miscommunication made the diagnostic process even more challenging, as was the case when Bethany was asked about stretch marks by her family doctor:

I remember my family doctor asking me at one point, do you have stretch marks? And I said, ‘no, I don’t have stretch marks. Last time I had them was when I was pregnant. And that was many years ago.’ But he didn’t describe the stretch marks. I was thinking of the pregnancy stretch marks with the fine white lines. And he must have thought about Cushing’s with the striae that are wide and purple. But there was no description of them. If I had [a description], I would have shown them immediately!

Christy noted how phone appointments may have negatively impacted her diagnostic process:

All of this went down in the [COVID-19] pandemic, so I actually never met a doctor in person about this ever. … I explain the weight gain I’m like kay I was 110. Now I’m 230 and these are the bursts. These are when it happened. Um, but they actually never saw me, not once, not even over zoom it was all over the phone … When I explained how much I gained they were just like, no.

In general, participants felt like they were not receiving the care they hoped for from their primary care provider. For example, Abby said that “Cushing’s patients have a lot of things going on and most regular doctors when they see you…they think you’re a hypochondriac because there’s always something wrong with [you].” Participants perceived their primary care providers as missing the big picture. Darby recognized that “I think each time I went into the doctor for the different things, … I would go in for specific things, but we never sort of put them all together as to what it was.” In describing her frustration with this process, Emily said: “And I’m just like how many other people are struggling with stuff like this, and they just get [dismissed].” Together, this miscommunication contributed, in part, to the delayed diagnosis, as it took time for providers to recognize the possible diagnosis of Cushing’s.

Medical gaslighting. Medical gaslighting is the process by which medical professionals will downplay, dismiss, or silence a patients’ view of their illness [26]. Abby described her experience with the first primary care provider she consulted: “he basically told me that I had mental baggage, and it was that I was a head case and that was my problem.” After moving to a different city, she described the next provider she met with as having a similarly dismissing response: “I also explained to her what was going on. I said I think there’s something wrong, I exercise and the harder the exercise more I gain weight. She basically said you’re not trying hard enough and suggested the South Beach diet to me.” Besides their weight, other symptoms were also dismissed. Emily said:

It was always passed off as oh, your high-stress job, high-stress family life, you’re depressed; those were always the comments to me. You’re just depressed, you’re just anxious because of this stuff and blah blah, blah. … As time went on the symptoms started multiplying. So, I’m like it’s not just not sleeping and depressed and anxious I’m like… my resting heart rate is in the 160’s without moving um, my vision’s starting to get impaired, I feel like I’m crazy, um and then the weight gain started. And once again they just said oh you know take up, take up cycling. That’s what the doctor told me.

In describing her experiences with feeling downplayed or dismissed, Honey stated:

I had swollen hands and feet, too, so he said, Well, you’re gonna have to get your diet under control, and I said well my diet is really good actually and I’ve been going to weight watchers for a year, haven’t dropped a pound, so there’s an issue there. And again, he would just chalk it up to PMS.

Honey also experienced skin sensitivities and was told she simply needed to use sunscreen more frequently. During the diagnostic process, Christy experienced medical gaslighting when completing her 24-hour urine free cortisol test:

I did the test and waited months again for my results. And then it came back super high. And so, he accused me of doing the test wrong. He said there’s no way um this makes sense. You need to do the test again. So, then I did the test again. And it was high again. And he accused me of doing it wrong again. And I was like, I’m telling you like I don’t know what you, I’ve got the instructions in front of me. … And so I did it again, and it came back like again in the thousands. … I did feel like I was going nuts, the same way when he kept telling me I was doing the test wrong.

Patient misunderstanding of symptoms

Participants also described misunderstanding their symptoms, which highlights a further breakdown in patient-provider communication about their disease, as these misperceptions were not clarified for them upon diagnosis and treatment. Participants appeared to hyper-fixate on, and misunderstand, their weight gain. They also misunderstood other symptoms as related to weight. Emily noted this fixation on weight directly when she said: “In the very beginning I noticed the weight gain first to be honest.” Abby shared that she decided to approach a health professional because of her weight gain:

I was a happy, healthy active athletic person, and all of a sudden something in my life happened where I just kept gaining weight and gaining weight. No matter how much like exercising or eating properly that I had done… The catalyst for me going to the doctor was, um, I noticed a bunch of stretch marks on my stomach and to me that was a sign of like rapid weight gain in such a small amount of time.

Like Abby, other participants misunderstood their weight gain and attempted to engage in behavioural changes to reverse this process. Bethany said:

Thankfully I did not have a doctor that told me to go and exercise and eat less. But when you did that, you still gained weight. The more I exercised, the more walking I did, the less I ate, the more I gained and the rounder the face got. And the more hair I lost.

Similarly, Christy described her weight gain as the catalyst behind her decision to hire a personal trainer:

I kind of decided based on super significant weight gain that I was going to invest in a personal trainer… So, I was with the personal trainer for about three months, and was only gaining weight, like I was cutting calories and working out I think it was like 12 times a week. … But everything was just getting worse. Like I was weaker, I couldn’t do things the same way that I used to, like the stretch marks were nuts I kept gaining weight I didn’t know why, despite still I was still walking every day and doing what I could.

When describing their experience of symptom onset prior to receiving their diagnosis, participants understood many of their physical changes as connected to their weight gain. This was especially true for those experiences that surrounded muscle weakening and movement, despite these being Cushing’s symptoms that are independent from weight. Bethany recalls how, when called for her appointment in her primary care provider’s waiting room, she “staggered to stand up and was almost immobile to a point, I was so big,” an experience she attributed to her weight gain. As symptoms worsened, participants felt disconnected from their bodies. Emily said: “I can’t trust [my] own body,” and Christy felt “so exhausted” because “of course that’s exhausting. Like, carrying all that [weight] around is tiring. Like, if you’re not exhausted, that would be weird.”

Participants also noted a misunderstanding of other Cushing’s symptoms, both alongside and independent of their weight gain. In recognizing the impact of stress on her symptoms, Honey said:

I opened a business, and the stress came back because of that, and then everything came to a head. Then I got the bruising, then I got the buffalo shoulders, then I got the big moon face. … People were starting to say, like is your whole life okay? It was kind of insulting. And then I got the big belly, and it just got bigger and bigger, and within 3 weeks I had gained 25lbs.

Darby noted that, in the fullness of her busy life, it was easy to explain away her symptoms:

I didn’t acknowledge what was going on it, I just didn’t push to find out why. I was always able to find a reason in my own brain or my own thinking as to all, you know. You know, I’m just I’m working too much and this will pass, and then it’ll get better. Or, you know, when I was falling down for no reason, it was like oh man you just got to pay more attention. All right, you know, I need to eat better because I’m not, you know, exercising. When I was gaining the weight and went to weight watchers and some reason the weight wasn’t coming off. … And I’m thinking, I’m doing all the right stuff.

Similarly, Franny described how she perceived her symptoms to be related to anxiety:

Oh, it’s just anxiety you’re always… It’s like the palpitations Oh, it’s just you’re nervous about something. … I guess I just… in my case, like I haven’t… maybe they caught it so soon enough that, like I haven’t really got to the point where like I’m I’m feeling a lot of symptoms?

Experienced weight stigma

Participants described numerous experiences of weight stigma in healthcare while seeking a diagnosis. Invalidation occurred when patients’ personal accounts of their illness were dismissed or not taken seriously, as described in the Lack of Patient Centered Care sub-themes. While many participant experiences of medical gaslighting can also be regarded as experiences of weight stigma, these themes were differentiated by whether or not participants reported they were dismissed or silenced, consistent with the definition of gaslighting [21].

Participants contributed their negative experiences, at least in part, to their weight. Participant’s felt like there was a significant difference in how they were treated by practitioners before the onset of their Cushing’s symptoms. Christy contrasted her experiences in healthcare pre- and post- Cushing’s: “When I went to the doctor and I was concerned about something as a kid, nobody ever doubted me like. And yeah, since then … people in general just don’t get [taken] seriously looking the way that I do. And don’t respect me as much it seems.” Although Christy spoke of “people in general,” this sentiment included her primary healthcare provider. Similarly, Honey described a perceived change in her relationship with her primary care provider pre- and post- Cushing’s onset and felt that her weight contributed to this change. She described her once positive relationship as one that is now associated with hurt:

Prior to Cushing’s my doctor was very forthcoming. I would tell him what I needed if I needed, felt I needed blood work, or felt I needed anything, or suggested that I…. maybe he’s not the one to help me that I need to see a specialist he would send me on to that specialist. So, yes, I always felt hurt by him.

Abby summarized participants’ experiences when she said: “Judging books by covers that’s, that’s what the healthcare system seems to do and I do feel that, like some of my treatment was definitely due to my body [size] and what, what they preconceived that I was a fat person, so it was my fault.” Franny described having requested her entire medical file and that seeing herself repeatedly referred to as a “morbidly obese female” in emails and other communication had a negative impact on her body image and self-esteem.

Diagnosis as a golden ticket

Post-diagnosis, participants experienced a profound sense of relief and validation, perceived themselves to be lucky to have received a diagnosis, and were thankful for the subsequent treatment they received. Bethany said: “once you get a diagnosis, it doesn’t matter what the diagnosis is, you’ve got a diagnosis and now we work towards that. Let’s correct it”. Christy felt like “Having that diagnosis under my belt was like a golden ticket … everything was easier.” Abby declared that the doctor who officially diagnosed her saved her life: “She had taken the time to like, say I believe you. Instead of just seeing a fat person and blaming it on me, which is really what the healthcare system does. Really it ruins people.” After waiting three years for a diagnosis, Darby stated that she felt “very lucky” and said:

From when my doctor said to me ‘I think it’s Cushing’s’ to when the actual diagnosis was, it was fast. It was weeks. It was, it was very, very quick. …Once we actually knew what it was to actually being able to have the surgery to have the tumor removed and start reversing the process of what was going on with my body. So. I was very lucky.

In hindsight, participants noticed there was a difference in how they were treated by healthcare professionals pre- and post-diagnosis. Abby said: “I firmly believe that there is a correlation there between how I was treated before, and then how I was treated after.” She elaborated to say that: “people have to believe me now, because a specialist has said, ‘This is what I have, and you may not understand it, but I do’.” Emily noted that “after I got the diagnosis my family doctor was very, very open, and caring with moving forward. And he commended me for pushing and knowing that things were wrong, and he was really good about it, and he apologised that it took long to get figured out.” Honey also noted” “I’d have to say like during the diagnosis, not great, but since I’ve had my pituitary tumor removed great, the aftercare has been fantastic.”

Discussion

Across seven semi-structured interviews with women with endogenous Cushing’s, the results of our preliminary inquiry into the lived experience of patients suggest that both patients and providers struggle to understand the progressive and individualized presentation of Cushing’s. This struggle can come, unintentionally, at the expense of patient centered care in the form of provider miscommunication, medical gaslighting, and weight stigma. Our results also suggest that diagnosis is viewed by patients as an important turning point for both effective treatment as well as reduced stigma.

Overall, the results of our study highlight the importance of patient centered care. Participants reported miscommunication, invalidation, weight stigma, and gaslighting in their healthcare encounters, all of which are contrary to the goals of patient centered communication [11, 12]. These findings are consistent with previous research identifying structural, educational, and resourcing barriers to patient centered communication [11, 27]. These barriers include understaffing, specific healthcare settings (i.e., acute care), limited time, insufficient communication, lack of training in patient centered communication, and inadequate patient education [11, 27]. Given that patient engagement is associated with improved outcomes, a better understanding of their condition, and more awareness of resources, [27] identifying strategies to enhance patient centered communication are of critical importance. Researchers have identified staffing longevity as associated with greater engagement and less burnout [27] and have identified provider training and professional development as significant in the implementation of patient centered communication [12]. Thus, in addition to patient centered communication skills, providers require knowledge of weight stigma and Cushing’s as well as appropriately resourced work environments to enact patient-centered care. However, an important responsibility falls to broader healthcare systems to empower providers by providing comprehensive training, addressing provider burnout, and changing healthcare culture and systems to allow for increased engagement in patient centered communication [12].

The rare occurrence [6, 7] and non-specific presentation [8] of endogenous Cushing’s is a unique barrier to patient centered communication. Participants in this study recognized the impact that the rare occurrence of their disease had on their provider’s misunderstanding of their symptoms. Bethany noted one interaction whereby her primary care provider mentioned being told in medical school that they would never see a case of Cushing’s in their careers. However, knowledge of Cushing’s is a pre-requisite for early detection [6]. Such knowledge is important, as overlooking endogenous Cushing’s is associated with increased mortality rates due to hypertension, metabolic diseases, and bone-related complications, with continued cardiovascular risk persisting after treatment [8].

An additional barrier to patient centered care highlighted in our results is weight stigma. Our findings are consistent with previous qualitative research on experienced weight stigma in healthcare contexts [28,29,30,31]. In previous research, patients have consistently reported the attribution of presenting concerns by healthcare providers to weight without a full exploration of the issue as well as poor verbal and non-verbal communication [28,29,30,31]. Such experiences with poor quality communication and stigmatization from healthcare providers are associated with subsequent patient healthcare delay and avoidance, [15, 17] and may contribute to increased internalization of weight stigma [32]. Our results highlight that, for patients with endogenous Cushing’s, weight stigma may be a contributing factor in the consistently reported delays to diagnosis, [6, 7] due to stereotyped assumptions about weight gain coupled with a lack of knowledge about Cushing’s, among providers as well as patients. Although participants in this study reported symptoms beyond weight gain, they perceived their weight as having an impact on their healthcare encounters.

Our findings related to weight stigma highlight the potential harm of weight- and appearance-focused sociocultural discourses [21, 22] on Cushing’s-related healthcare. For patients, internalization of these discourses may have contributed to the extent to which they understood symptoms such as fatigue and muscle weakening as caused by their weight gain. For providers, this may have contributed to their clinical impressions and decision-making. Researchers have previously identified weight and appearance discourses as contributing to a weight-centric practice paradigm, whereby higher weights are regarded as within individual control as well as the cause of poor health [33]. Within a weight-centric paradigm, recommending weight loss is regarded as an effective health-promoting solution and failure to achieve or sustain weight loss is regarded as the fault of the patient. Criticisms of the unintended consequences of a weight-centric paradigm have prompted researchers to call for a weight-neutral approach to healthcare that recognizes and addresses weight stigma, assesses cardiometabolic and lifestyle health risks in patients across the weight spectrum, and seeks to promote the health of patients independent of changes in weight status [33].

This research was conducted as a preliminary inquiry into the lived experience of patients with Cushing’s, given the lack of such research in the literature. Our findings suggest that patient experiences are an important, but unexplored, line of inquiry and that more research is needed in this area. Given that lived experiences may differ across contexts and may vary by an individual’s culture, race, relationship status, and/or geographical location, further research is needed with larger samples to elucidate the potential impact of provider miscommunication, medical gaslighting, and weight stigma on the experiences of patients with Cushing’s throughout the diagnostic and treatment process. Future research examining Cushing’s-related healthcare experiences access gender and racial identities is also needed to fully understand the broad experiences of patients with this disease.

Limitations

To our knowledge, this is the second study to examine the lived experiences of people with Cushing’s, with only one other qualitative study examining the impact of Cushing’s on quality of life, published in Italian [34]. However, this is the first study to examine patients’ lived experiences in healthcare, as this previously published Italian study examined patients’ perceived quality of life. Despite this novelty and strength, this research is not without its limitations. First, as only seven women with Cushing’s were recruited, this preliminary inquiry is limited by sample size. Thus, the results are not generalizable to all women with Cushing’s, their healthcare providers, or their experiences in healthcare. Second, given that our participants were recruited from an online support group, their reported experiences may be different from those who have not sought such support from the online patient community. Third, our sample was limited in demographics. All participants identified as white women but did represent a broad range in age and socioeconomic status. Finally, as our participants reported a delay to diagnosis of 1.5 to 3 years, their experiences may not represent those of individuals who experienced a longer delay to diagnosis.

Conclusion

The findings of this research indicate that a lack of patient centered care may have an impact on the recognition and referral/diagnosis of Cushing’s in primary healthcare settings. Our results highlight an important area of inquiry that warrants further attention. Given the small sample size, further research is needed to clarify and to expand on these findings. However, these results highlight the importance of patient centered care and curious investigation into the causes of unexpected and uncontrollable weight gain in patient encounters.

Data availability

Data for this study is available on reasonable request to the corresponding author.

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Acknowledgements

Not applicable.

Funding

SCJ was supported by a Jamie Cassels Undergraduate Research Award.

Author information

Authors and Affiliations

Department of Psychology, University of Victoria, 3800 Finnerty Rd, Victoria, BC, V8P 5C2, Canada
Sarah C Jones
Educational Psychology and Leadership Studies, University of Victoria, 3800 Finnerty Rd, Victoria, BC, V8P 5C2, Canada
Sarah Nutter
Institute on Aging and Lifelong Health, University of Victoria, 3800 Finnerty Rd, Victoria, BC, V8P 5C2, Canada
Sarah Nutter
Brigham and Women’s Hospital, 75 Francis St., Boston, MA, 02115, USA
Jessica F Saunders

Contributions

SCJ and SN conceptualized the study. All authors contributed to the study design and SCJ conducted all interviews and transcriptions. Data analysis was conducted by SCJ and SN with support from JFS. All authors contributed to manuscript preparation.

Corresponding author

Correspondence to Sarah Nutter.

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Ethics approval and consent to participate

This study received ethics approval from the Human Research Ethics Board at the University of Victoria (#21–0507). Informed consent was received from all participants.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Cushing’s Syndrome Masquerading as Fibromyalgia: A Case Series

Posted on September 2, 2024 by MaryO

Abstract

Three young female patients with a history of generalized body pain were diagnosed with fibromyalgia. They visited several specialities which related patients’ symptoms to their previous diagnosis of fibromyalgia and were treated symptomatically. These patients developed a multitude of clinical features including fractures, hypertension, abnormal weight gain, proximal myopathic pain and bruising. They were seen by rheumatologists whose assessment was that their clinical features were not entirely due to fibromyalgia and suspected that patients have a possible underlying endocrine cause. Patients were referred to an endocrinologist for further tests with suspicion of Cushing’s syndrome. Laboratory tests and imaging confirmed a diagnosis of Cushing’s syndrome. Two of them had adrenal adenoma and one had iatrogenic corticosteroid use. These cases emphasize the need for thorough clinical evaluation for patients who are thought to have fibromyalgia. Fibromyalgia is a diagnosis of exclusion.

Introduction

Fibromyalgia is a chronic functional neurosensory disorder characterized by diffuse musculoskeletal pain, fatigue, and insomnia [1]. The exact cause is yet to be understood and the diagnosis relies solely on the patient’s history as physical examination, imaging, and laboratory tests are usually normal making it a diagnosis of exclusion.

Cushing’s syndrome is an endocrine disorder caused by an increase in cortisol level in the body due to either exogenous glucocorticoid administration or endogenous overproduction of cortisol due to adrenal adenoma, pituitary adenoma, or ectopic paraneoplastic foci [2].

Patients may present with central obesity, easily bruised skin, purple abdominal striae, osteoporosis and pathological fractures, secondary hypertension, hyperglycemia, fatigue, and proximal muscle weakness.

We herein report three cases of patients who had diffuse muscle pain and were misdiagnosed as fibromyalgia without ruling out endocrinological causes such as Cushing’s syndrome which they were found to have.

Case Presentation

Case report 1

A 38-year-old Egyptian female with a history of fibromyalgia presented to the urgent care in November 2020 with right little toe pain and swelling after hitting it against the wall. She had a fracture of the distal phalanx of the fifth toe (Figure 1) and was managed conservatively.

$X-ray-of-right-foot-showed-fracture-at-the-distal-phalanx-of-fifth-toe-with-suspected-intra-articular-extension$

Figure 1: X-ray of right foot showed fracture at the distal phalanx of fifth toe with suspected intra-articular extension

In January 2022, she presented to her gynaecologist with headache, body swelling and was found to be hypertensive (156/105mmHg). She was referred to cardiology for management of hypertension, who recommended keeping a blood pressure (BP) diary with one-week follow-up as her BP was high on one occasion only.

In May 2022, she visited an internist because of easy bruising for six years in both lower limbs and history of bleeding following dental procedure. She was also complaining of gaining weight (15 kg over seven months). Investigations including coagulation profile, serum electrolyte, blood glucose, liver enzymes, and autoimmune antibodies were ordered, and they were normal. Patient was reassured and was diagnosed as purpura simplex.

In September 2022, she had a visit to the cardiologist after she was diagnosed with hypertension in Egypt and was on ramipril (2.5mg) and torsemide (10mg). The cardiologist continued ramipril and discontinued torsemide. The cardiologist referred her to internal medicine because of her history of fibromyalgia, and review of her prescribed medications from Egypt which included duloxetine, hydroxychloroquine (HCQ), and melatonin.

She had multiple visits to internists between September 2022 and March 2023 with complaints of body swelling, generalized joint stiffness, hip pain, proximal myopathic pain when lifting arms or standing up with oral ulcers and small reddish-purple spots just beneath the skin’s surface most likely purpura simplex. Laboratory tests were ordered, and they showed she had low serum potassium and positive antinuclear antibody (ANA) titer (DFS-70 pattern). Also, she had negative rheumatoid factor (RF), extractable nuclear antigen (ENA) panel, antineutrophil cytoplasmic antibodies (ANCA) and anti-cyclic citrullinated peptide (CCP) with normal C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). She was given potassium supplements and magnesium. During her visits she was prescribed various medications for fibromyalgia including duloxetine, amitriptyline, and tramadol. She also developed back pain and her MRI of sacroiliac joints showed signs of left-sided linear sacrum fracture, crescentic subchondral edema in the right femoral head suggestive of avascular necrosis (AVN) and narrowing of L5/S1 intervertebral disc space with degenerative changes (Figure 2).

$MRI-sacroiliac-joints-showed-left-sided-linear-sacrum-fracture$

Figure 2: MRI sacroiliac joints showed left-sided linear sacrum fracture

She then visited an orthopedic surgeon in April 2023 with back and right hip pain. The orthopedic doctor thought that her symptoms and signs were not entirely consistent with fibromyalgia, and she was referred to rheumatology for further review.

On rheumatology review she gave a history of whole-body pain, back pain, severe right hip pain, two fractures (left foot and sacrum), hypertension, hypokalaemia, amenorrhea for 18 months, weight gain (of 15 kg over seven months) and skin bruising. Laboratory tests showed negative autoimmune tests, low serum potassium, high alkaline phosphatase (ALP), normal parathyroid hormone (PTH), Mg, vitamin D and calcium. She was referred to internal medicine for low serum potassium, with suspicion of adrenocortical excess.

Her internist suspected Cushing’s syndrome as her physical examination showed that she was obese with florid purple striae on the trunk and arms in addition to proximal muscle weakness . He then ordered investigations that showed low adrenocorticotropic hormone (ACTH) using electrochemiluminescence immunoassay (ECLIA) of <1 pg/mL (normal range 7.2-63.3 pg/mL), and high serum cortisol using chemiluminescence microparticles immunoassay (CMIA) at 5 pm of 604.03 nmol/L (normal range 79.0-478 nmol/L). Her cortisol before 10 am that was collected at 9:02 am was 623.91 nmol/L (normal range 101-536 nmol/L). In view of these values, she was referred to the endocrinologist. Serum aldosterone, renin, and their ratio were all normal. 24-hour urinary cortisol was inconclusive because of low volume of urine. Luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), prolactin, metanephrines and normetanephrines were normal. It was planned to do overnight dexamethasone suppression tests (ODST), but patient travelled to Egypt.

CT abdomen showed a 3.2×2×3 cm well-defined lesion arising from the junction between the arms of the right adrenal gland showing inhomogeneous density with inhomogeneous enhancement after IV contrast administration with delayed washout, the maximum enhancement after the IV contrast administration at the portal phase about 55 Hounsfield units (HU) indicating a right adrenal adenoma (Figure 3). CT sacrum showed fragmented fracture inferior ramus of right pubic bone associated with callus formation and significant fragmented fracture lateral part of superior ramus of right pubic bone associated with callus formation (Figure 4). MRI hips showed avascular necrosis of the right femur head (stage II according to Ficat and Arlet classification) (Figure 5), which was treated with core decompression surgery.

CT-adrenal-showed-a-3.2×2×3-cm-well-defined-inhomogeneous-density-lesion-arising-from-the-junction-between-the-arms-of-the-right-adrenal-gland-consistent-with-adrenal-adenoma

Figure 3: CT adrenal showed a 3.2×2×3 cm well-defined inhomogeneous density lesion arising from the junction between the arms of the right adrenal gland consistent with adrenal adenoma

$CT-pelvis-showed-fragmented-fracture-at-the-inferior-and-superior-ramus-of-right-pubic-bone-associated-with-callus-formation.-Subcortical-ill-defined-lytic-area-is-noted-at-the-right-humeral-head-surrounded-with-sclerotic-reaction-could-be-due-to-avascular-necrosis-(AVN)$

Figure 4: CT pelvis showed fragmented fracture at the inferior and superior ramus of right pubic bone associated with callus formation. Subcortical ill-defined lytic area is noted at the right humeral head surrounded with sclerotic reaction could be due to avascular necrosis (AVN)

MRI-of-the-pelvis-showed-subcortical-geographic-area-at-the-right-femoral-head-with-inhomogeneous-signal-intensity-(edematous-and-sclerotic-changes)-mostly-due-to-avascular-necrosis-(stage-II-according-to-Ficat-and-Arlet-classification)

Figure 5: MRI of the pelvis showed subcortical geographic area at the right femoral head with inhomogeneous signal intensity (edematous and sclerotic changes) mostly due to avascular necrosis (stage II according to Ficat and Arlet classification)

She had the surgery to remove the adrenal adenoma in Egypt and histopathology confirmed the diagnosis. She was then started on corticosteroids as she had low serum cortisone levels after her surgery. Currently she is also taking duloxetine and calcium/vitamin D. She developed a fracture at the right femoral neck after a fall and had hip replacement in Egypt (Figure 6).

Figure 6: X-ray of the right hip joint showed signs of right hip joint replacement

Case report 2

A 47-year-old Bangladesh female presented with a complex array of symptoms initially suggestive of fibromyalgia. The patient reported chronic widespread muscle and joint pain, with identification of approximately eight tender points during examination. These symptoms, coupled with fatigue, were initially thought to be fibromyalgia due to their nonspecific nature. Subsequently, the patient started to have multiple bone fractures. In total she had six fractures over one year including fractures of the superior and inferior pubic ramus on the left side, right metatarsal bone fracture, fracture of the left proximal shaft of the fifth metatarsal, fractures of the shafts of the third and fourth left metatarsal. She has been reviewed by multiple physicians. A deeper look at her medical history revealed that despite the absence of overt Cushingoid features, she has several medical problems, including newly diagnosed hypertension and type 2 diabetes mellitus (hemoglobin A1C (HbA1C) 7.3%), raising the possibility of an underlying endocrine disorder. Psychiatric concerns involve a history of anxiety, insomnia, and major depressive disorder, with medication adjustments made independently. In addition, the patient reported irregular menstrual cycles, further complicating the clinical picture. Subtle signs such as unexplained central weight gain and telangiectasia prompted further endocrine evaluation.

Elevated morning cortisol levels and non-suppressed cortisol on an overnight 1 mg dexamethasone suppression test with high am cortisol, low am ACTH, ODST showed non-suppressed cortisol >400, and >500 on two occasions, and 24-hour urine free cortisol is high = 483 nmol (28-138). Adrenal CT without contrast revealed a well-defined heterogeneous isodense-to-hypodense lesion in the left adrenal gland, measuring 3.2 x 2.4 cm with a density of 16 HU, indicative of an adrenal adenoma. Imaging also identified old fractures of the left 10th rib and transverse processes of L1 and L4, which were previously undocumented and suggested underlying bone fragility.

The combination of subtle endocrine symptoms, nonspecific musculoskeletal pain, and psychological components initially led to a misdiagnosis of fibromyalgia. However further endocrine investigation confirmed Cushing’s syndrome due to an adrenal adenoma (Figure 7).

Figure 7: CT adrenal showed a 3.2 x 2.4 cm well-defined hypodense lesion in left adrenal gland

The patient underwent successful laparoscopic removal of the left adrenal adenoma. Post-operatively, the patient developed adrenal insufficiency, necessitating a carefully managed hydrocortisone tapering regimen. Management of diabetes, hypertension, and psychiatric symptoms continued, with adjustments anticipated in response to changes in endocrine status post-adrenectomy. The patient was started on calcium and vitamin D supplementation to address the secondary osteoporosis.

Case report 3

A 35-year-old Emirati woman with a medical history of hypothyroidism, asthma, obstructive sleep apnea, scoliosis, secondary degenerative lumbosacral changes from a previous accident, and migraines sought consultation at the Department of Rheumatology.

She reported a two-year history of polyarthralgia, proximal muscle weakness, profound fatigue, and peripheral edema. BP was 148/88. Physical examination revealed a round face, dorsocervical fat pad, central obesity, and puffy hands and feet.

Laboratories revealed hemoglobin (Hb) 13 g/l, creatinine kinase (CK) normal, while CRP was high (7 mg/l). Weakly positive anti-NOR 90 antibodies were found and noted to have unclear etiology with no clinical manifestation of scleroderma. Vitamin D deficiency was corrected (level: 47 nmol/L, normal range 50-150 nmol/L), and hypothyroidism medication was adjusted (TSH 7.7 IU/L, T4 9, normal range 12-22).

Despite extensive evaluations, including bilateral hands and feet X-rays, MRI of the hand, PET scan and laboratory assessments, the etiology of her symptoms remained elusive. Following a provisional diagnosis of fibromyalgia, the patient was managed symptomatically with medications, including pregabalin, amitriptyline, and duloxetine for one year. However, her symptoms persisted.

Further investigations revealed low serum cortisol levels: a morning cortisol level of 20 nmol/l (64-536), ACTH <0.3 pg/ml (1.6-13.9), and a 24-hour urine cortisol level of 11 nmol (28-138 nmol). Dual-energy X-ray absorptiometry (DEXA) scan demonstrated low bone mineral density with highest value at the lumbar sites (L2-L4), with a T-score of -2.4. Upon detailed review, it was noted that the individual had a history of frequent injections in both sacroiliac and lumbar facet joints, as well as trigger point injections ranging from 80-120 mg, administered every two to three months over a period of two years. Given the overall picture, with adequate adrenal response to synacthen test (the synacthen test results were as follows: baseline ACTH level was 1.2 pmol/L, rising to 0.8 pmol/L at 30 minutes and 0.4 pmol/L at 60 minutes; corresponding cortisol levels were 52 nmol/L at baseline, increasing to 433 nmol/L at 30 minutes and 472 nmol/L at 60 minutes), this was correlated with the diagnosis of iatrogenic Cushing’s syndrome.

A summary of the cases is in Table 1, and the timeline of the cases is in Table 2.

Case	Age	Gender	BMI	Steroid (Exogenous vs Endogenous)	HTN	DM	Hyperlipidemia	Psychiatric symptoms	Fracture	Abnormal Test Results	Treatment
Case 1	38	F	31.4	Endogenous- adrenal adenoma	Yes	No	No	No	Four fractures	Low potassium, low ACTH (<1pg/mL), high serum cortisol (604.03 nmol/L)	Adrenal adenoma surgical resection
Case 2	48	F	26	Endogenous- adrenal adenoma	Yes	Yes	Yes	Depression on Rx	Six fractures	Low ACTH (<0.3 pmol/L), high serum cortisol (1104 nmol/L), 24-hour urine free cortisol is high = 483 nmol (28-138)	Adrenal adenoma surgical resection
Case 3	35	F	38	Exogenous	Yes	No	No	Depression and anxiety on Rx	–	Low serum cortisol 20 nmol/l (64-536), low ACTH <0.3 pg/ml (1.6-13.9), 24-hour urine cortisol 11 nmol (28-138).	Refrain from injection

Table 1: Summary of patients with Cushing syndrome who presented with fibromyalgia

F: female, HTN: Hypertension, DM: Diabetes Mellitus, Rx: Treatment, ACTH: Adrenocorticotropic hormone

Case	Timeline of clinical features	Final diagnosis date
Case 1	Bruises, myalgia, body pain since 2016; headache, body swelling since 2020; hypertension since 2021; hip pain since Jan 2022; fractured toe in Nov 2022; fracture of pubic rami discovered incidentally in April 2023; avascular necrosis of right hip in April 2023	May 2023 she was diagnosed with Cushing syndrome due to adrenal adenoma
Case 2	Widespread muscle and joint pain in 2017; hypertension and type 2 diabetes mellitus in 2019; multiple fractures in 2020-2021; anxiety, insomnia, and major depressive illness in 2020; menstrual irregularities in July 2021	November 2021 she was diagnosed with Cushing syndrome due to adrenal adenoma
Case 3	Polyarthralgia, proximal muscle weakness, profound fatigue, and peripheral oedema in 2021-2023; depression and anxiety in 2022; hypertension in 2023; low bone mineral density in 2023	June 2023 exogenous Cushing syndrome

Table 2: Timeline of the three cases

Discussion

Fibromyalgia is a multifactorial painful body disorder with several hypotheses regarding its etiology and pathophysiology such as increased pain sensitivity, neuroendocrine axis dysregulation, hypermobile joints, poor physical fitness, as well as genetic predisposition and environmental triggers [3].

Fibromyalgia and Cushing’s syndrome are distinct medical conditions, but they can share some common symptoms such as fatigue, muscle weakness, mood changes, sleep disturbances, and memory deficits. Because of the multiple symptoms that are present in both, a patient could be misdiagnosed with fibromyalgia instead of Cushing’s syndrome if proper history-taking, physical examination and relevant investigation are not pursued. Fibromyalgia is a diagnosis of exclusion, so effort should be made to look for any possible cause of the patient’s symptoms before making a diagnosis of fibromyalgia. According to the American College of Rheumatology, a patient must satisfy these three conditions to be diagnosed with fibromyalgia: widespread pain index (WPI) ≥7 and symptom severity (SS) scale score ≥5 or WPI 3-6 and SS scale score ≥9, symptoms have been present at a similar level for at least three months, and the patient does not have a disorder that would otherwise explain the pain [4].

According to the 2008 Endocrine Society guidelines, Cushing syndrome’s diagnosis is made by lab tests that show consistently high production of cortisol using 24-hour urine free cortisol level, low-dose (1mg) dexamethasone suppression test, or late-night salivary or serum cortisol [5].

A literature review was performed using PubMed and Google Scholar databases. Search terms included “fibromyalgia” and “Cushing’s syndrome” to which five results were shown. Out of the five results, only one case report had slight relevance to our two cases which was about a 39-year-old woman previously diagnosed with Cushing’s disease who developed fibromyalgia [1]. Unlike our cases, she was already diagnosed with Cushing’s disease. Several cases of iatrogenic Cushing’s syndrome are widely recognized [6-10]. Although intra-articular corticosteroid injections are uncommon causes, they are becoming increasingly recognized especially in patients who have received multiple or relatively high doses [11-13].

Our patients saw different physicians from various specialties and had multiple hospital visits over two to three years. They were originally diagnosed with fibromyalgia. Despite a multitude of other symptoms and signs such as fractures, weight gain, amenorrhea, easy bruising, and hypertension, the initial diagnosis of fibromyalgia was carried forward by multiple physicians without proper re-evaluation, resulting in only symptomatic treatment. These cases highlight the importance of thorough clinical evaluation and a holistic approach to patients who present with fibromyalgia symptoms even if a previous diagnosis of fibromyalgia has been made.

Conclusions

These cases underscore the challenges in differentiating Cushing’s syndrome from other conditions, particularly when presenting with nonspecific symptoms similar to fibromyalgia. Heightened clinical suspicion, thorough evaluation, and consideration of medication histories are essential. A high index of suspicion, combined with targeted radiological and biochemical testing, is crucial for accurate diagnosis and effective management.

References

Ohara N, Katada S, Yamada T, et al.: Fibromyalgia in a patient with Cushing’s disease accompanied by central hypothyroidism. Intern Med. 2016, 55:3185-90. 10.2169/internalmedicine.55.5926
Sharma ST, Nieman LK, Feelders RA: Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015, 7:281-93. 10.2147/CLEP.S44336
Coles ML, Weissmann R, Uziel Y: Juvenile primary fibromyalgia syndrome: epidemiology, etiology, pathogenesis, clinical manifestations and diagnosis. Pediatr Rheumatol Online J. 2021, 19:22. 10.1186/s12969-021-00493-6
Wolfe F, Clauw DJ, Fitzcharles MA, et al.: The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010, 62:600-10. 10.1002/acr.20140
Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
Psomadakis C, Tweddell R, Lewis F: Too much of a good thing? Iatrogenic Cushing syndrome secondary to excessive topical steroid use in lichen sclerosus. Clin Exp Dermatol. 2023, 48:429-30. 10.1093/ced/llac097
Jones W, Chastain CA, Wright PW: Iatrogenic cushing syndrome secondary to a probable interaction between voriconazole and budesonide. Pharmacotherapy. 2014, 34:e116-9. 10.1002/phar.1432
Fredman R, Tenenhaus M: Cushing’s syndrome after intralesional triamcinolone acetonide: a systematic review of the literature and multinational survey. Burns. 2013, 39:549-57. 10.1016/j.burns.2012.09.020
Sadarangani S, Berg ML, Mauck W, Rizza S: Iatrogenic cushing syndrome secondary to ritonavir-epidural triamcinolone interaction: an illustrative case and review. Interdiscip Perspect Infect Dis. 2014, 2014:849432. 10.1155/2014/849432
Sukhumthammarat W, Putthapiban P, Sriphrapradang 😄 Local injection of triamcinolone acetonide: a forgotten aetiology of Cushing’s syndrome. J Clin Diagn Res. 2017, 11:OR01-2. 10.7860/JCDR/2017/27238.10091
Tan JW, Majumdar SK: Development and resolution of secondary adrenal insufficiency after an intra-articular steroid injection. Case Rep Endocrinol. 2022, 2022:4798466. 10.1155/2022/4798466
Alidoost M, Conte GA, Agarwal K, Carson MP, Lann D, Marchesani 😧 Iatrogenic Cushing’s syndrome following intra-articular triamcinolone injection in an HIV-infected patient on cobicistat presenting as a pulmonary embolism: case report and literature review. Int Med Case Rep J. 2020, 13:229-35. 10.2147/IMCRJ.S254461
Kumar S, Singh RJ, Reed AM, Lteif AN: Cushing’s syndrome after intra-articular and intradermal administration of triamcinolone acetonide in three pediatric patients. Pediatrics. 2004, 113:1820-4. 10.1542/peds.113.6.1820

From https://www.cureus.com/articles/264073-cushings-syndrome-masquerading-as-fibromyalgia-a-case-series#!/

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Diagnostic Dilemma in Cushing’s Syndrome: Discrepancy Between Patient-Reported And Physician-Assessed Manifestations

Posted on August 12, 2024 by MaryO

Purpose

Early diagnosis and immediate treatment of Cushing’s syndrome (CS) are critical for a better prognosis but remain a challenge. However, few comprehensive reports have focused on this issue or investigated whether patient-reported manifestations are consistent with physician-assessed symptoms of CS. This study aimed to clarify the differences in patient-reported and physician-assessed manifestations of signs and symptoms of CS that prevent early diagnosis.

Methods

This single-center retrospective study included 52 patients with CS (16 with Cushing’s disease and 36 with adrenal CS). Upon clinical diagnosis, medical records were used to independently review the patient-reported and physician-assessed manifestations of typical (such as purple striae and proximal myopathy) and nonspecific features (such as hirsutism and hypertension). The correlations and differences between the patient-reported and physician-assessed manifestations were then analyzed.

Results

We observed a positive correlation between the total number of manifestations of nonspecific features reported by patients and those assessed by physicians, but not for typical features. Moreover, manifestations reported by the patients were less frequent than those assessed by physicians for typical features, leading to discrepancies between the two groups. In contrast, there were no differences in most nonspecific features between the patient-reported and physician-assessed manifestations. Notably, the concordance between patient-reported and physician-assessed manifestations of typical features was not associated with urinary free cortisol levels.

Conclusion

Regardless of disease severity, patients often do not complain of the typical features of CS that are crucial for formulating a diagnosis.

Introduction

Endogenous Cushing’s syndrome (CS) is caused by chronic and excessive glucocorticoid exposure. This occurs primarily due to adrenocorticotropic hormone (ACTH)-producing pituitary tumors (Cushing’s disease; CD) or cortisol-producing adrenal tumors (adrenal Cushing’s syndrome; ACS) [1]—and has a high mortality rate owing to cardiovascular disease, severe infection, and suicide, even when diagnosed and treated appropriately [1, 2]. Moreover, the prognosis is poor if the disease is not adequately treated or remains undiagnosed [2]. Therefore, early diagnosis and immediate intervention are important, as remission of CS due to surgical and pharmacological treatment can reduce the risk of mortality [3, 4].

CS is a rare disease with a prevalence of 57 per million individuals and an annual incidence of 3.2 per million, and its epidemiology is consistent across various regions worldwide [5, 6]. Most symptoms and signs of CS are common in general metabolic disorders, including obesity, hypertension, osteoporosis, and diabetes mellitus [7]. However, CS should be suspected if these symptoms appear as unusual features for their age [1, 8]. Consequently, the identification of CS is challenging and labor-intensive [1, 9, 10]. In fact, recent research revealed that a definitive diagnosis of CD (the most common form of CS), took an average of 3.8 ± 4.8 years from the onset of symptoms, and patients typically consulted 4.6 ± 3.8 medical professionals before this disease was identified [11]. Typical features of CS include symptoms of moon face, central obesity, or buffalo hump [12], which are similar to other symptoms such as primary obesity and therefore can lead to misdiagnosis. Furthermore, although purple striae or thin skin with an increased propensity for bruising are other typical features of CS [12], these attributes are not commonly acknowledged by the general population [1, 9].

Attempts have been made to diagnose CS early, including the development of scoring systems to estimate the pre-test probability of CS and facial image analysis software to diagnose the specific facial features of CS [13,14,15]; however, these have not yet been used widespread or fully and the early diagnosis of CS remains dependent on the experience-based medical skills of the clinical staffs [16].

Additionally, although it is difficult for patients to recognize complex and nonspecific symptoms [17, 18], the significance of patients recognizing their illness has recently been reported for various diseases such as heart failure and malignant carcinoma [19,20,21]. It is widely acknowledged that patients’ self-recognition can result in early detection of the disease, reduce its severity and recurrence, and enhance their quality of life [19]. In patients with endocrine diseases, there is increasing focus on issues surrounding self-recognition [22,23,24]. For example, a previous study focusing on acromegaly reported a discrepancy between patient-reported and physician-reported manifestations and indicated that resolving this discrepancy could shorten the time to diagnosis [25].

Identifying CS may be challenging for primary care physicians who are yet to specialize. Therefore, endocrinologists with extensive experience in CS have often noticed that patients and these physicians struggle to identify the symptoms of CS; however, few comprehensive reports have focused on this issue or investigated whether patient-reported manifestations are consistent with physician-assessed symptoms of CS.

Therefore, this study aimed to investigate the unreported manifestations of CS among individuals referred to non-specialist healthcare providers, including primary care physicians, and to recognize potential challenges with the current diagnosis of CS with the goal of facilitating early detection.

Materials and methods

Patients, study design, and data collection

This single-center retrospective study was conducted to identify the discrepancies between patient-reported and physician-assessed symptoms and investigate the factors causing these differences.

From September 2004 to December 2022, 199 patients were referred to our department at a tertiary medical institution upon suspicion, evaluation, or follow-up for hypercortisolism. Of these patients, 92 were newly diagnosed with CS (36 with CD, 51 with ACS, and 5 with ectopic ACTH syndrome) based on the diagnostic guidelines [3, 8, 12], with a diagnosis confirmed by pathological evaluation after surgical resection [26]. However, 35 patients were excluded due to a lack of detailed clinical data on the manifestations at diagnosis. Similarly, we excluded individuals diagnosed with ectopic ACTH syndrome because of the lack of comprehensive information on symptoms reported by the patients and primary care physicians due to the rapid progression and severity of this disease. Therefore, 52 patients (16 with CD and 36 with ACS) were enrolled in this study.

Upon clinical diagnosis, the manifestations included in the comprehensive standardized interview at the time of diagnosis and those assessed by the physician through collaborative assessment with multiple board-certified endocrinologists as routine practice were independently reviewed from the medical records. We categorized these manifestations reviewed from the medical records into the following two categories based on the diagnostic guidelines including those of the Japan Endocrine Society: typical features, including moon face, central obesity or buffalo hump, purple striae of ≥1 cm, thin skin and easy bruising, and proximal myopathy; and nonspecific features (shown as atypical in Japan Endocrine Society’s guideline), including hypertension, menstrual abnormalities, acne, hirsutism, peripheral edema, glucose metabolism impairment, osteoporosis, pigmentation (which is not expected in patients with ACS), and mental abnormalities [1, 8, 12]. Central obesity or buffalo hump can also be observed in pseudo CS. However, in this study, features were classified as the same typical feature according to clinical guidelines [12, 27]. We also reviewed the biochemical findings, comorbidities, duration from the initial recognition of CS-related symptoms to diagnosis, and number of medical institutions visited before diagnosis.

The present retrospective study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Kobe University Hospital (Approval No. 1351). The patients had the option of an opt-out process, and all procedures were part of routine medical care.

Definition of patient-reported and physician-assessed manifestations

In the context of routine clinical care, physicians asked the patients about the presence or absence of manifestations and comorbidities (e.g., hypertension, menstrual abnormalities, glucose metabolism impairment, osteoporosis, and mental abnormalities), which were documented in the medical records. These reports in the medical records were defined as patient-reported manifestations in this study. In contrast, the manifestations and comorbidities of CS were assessed within several weeks after the patient was referred to our department for suspected CS. Additional diagnostic information on comorbidities is provided in the subsequent section. Physician-assessed manifestations were subsequently defined based on these findings.

Comorbidities of Cushing’s syndrome

All comorbidities were diagnosed according to the appropriate guidelines [28,29,30]. For example, hypertension was diagnosed if patients were taking oral antihypertensive medication or had more than grade 1 hypertension (≥140/90 mmHg) in a treatment-naïve state [28]. Moreover, glucose metabolism impairment—including diabetes mellitus, impaired glucose tolerance, and impaired fasting glucose—was diagnosed based on the results of blood glucose levels during fasting and after a 75-g oral glucose tolerance test, as well as hemoglobin A1c (HbA1c) levels [29]. Patients taking medications for diabetes mellitus at the time of CS diagnosis were also categorized as having diabetes.

Other comorbidities included mental abnormalities, menstrual abnormalities, and the presence of osteoporosis. Mental abnormalities were defined as the use of anxiolytic medications, sleeping pills, or antidepressants prescribed by experienced psychologists, and menstrual abnormalities were defined as women with irregular menstrual cycles. Furthermore, the presence of osteoporosis was defined as bone mineral density (BMD) of <–2.5 standard deviations (SD) of the T-score of the lumbar vertebrae (L2–L4), femoral neck, or distal radius measured using dual-energy x-ray absorptiometry (DXA; Horizon A DXA System), and/or an experience of a fragility fracture [30]. As per the specifications of the measurement system employed, L1 was not included in the assessment. The Z-score was also employed as a diagnostic reference among young adults. Patients also diagnosed with osteoporosis who were receiving medications for this disease.

Hormone assay

In this study, blood samples were collected after an overnight fast. Subsequently, serum cortisol levels were measured using a chemiluminescent enzyme immunoassay [CLEIA] (TOSOH, Tokyo, Japan, RRID:AB_3099658) or enzyme immunoassay [EIA] (TOSOH, Tokyo, Japan, RRID:AB_3076600). Similarly, plasma ACTH levels were measured using a CLEIA (TOSOH, Tokyo, Japan, RRID:AB_3099657, or Siemens, Tokyo, Japan, RRID:AB_2909441) and EIA (TOSOH, Tokyo, Japan, RRID:AB_2783633). In both methods, the measurements showed good correlation and no conversion was required [31, 32].

Urinary free cortisol (UFC) levels were also measured using radioimmunoassays (RIA; TFB, Tokyo, Japan, RRID:AB_2894408) or chemiluminescent immunoassays (CLIA; Siemens, Tokyo, Japan, RRID:AB_2893154). Using the following formula, the UFC levels measured by RIA were then corrected to the value measured by CLIA: Y = 0.832X − 4.23 (Y = UFC levels using CLIA, X = UFC levels using RIA) [33].

Statistical analysis

All statistical analyses were performed using SPSS ver. 28.0 software (IBM Corp., Armonk, NY, USA). All continuous variables were analyzed using the Shapiro–Wilk normality test to confirm a normal distribution, whereas Fisher’s exact test was used to analyze categorical data. Between the two groups, differences in normally or non-normally distributed data were compared using the unpaired Student’s t-test or the Mann–Whitney U test, respectively.

Cohen’s kappa coefficient was used to describe the concordance between the patient-reported and physician-assessed manifestations. As previously reported [19, 20, 34], the concordance based on the value of Cohen’s kappa coefficient was rated as follows: 0.00–0.20 for “Slight,” 0.21–0.40 for “Fair,” 0.41–0.60 for “Moderate,” 0.61–0.80 for “Substantial,” and 0.81–1.00 for “Almost Perfect.” For correlation analysis between two variables of non-normally distributed data, we used Spearman’s rank correlation coefficient. Multivariate logistic regression analyses were then performed to investigate variables associated with the discrepancies between patient-reported and physician-assessed manifestations.

The results are presented as mean ± SD for normally distributed data and median [interquartile range] for non-normally distributed data, and differences were considered statistically significant when the P value was <0.05.

Results

Clinical characteristics of the patients

We included 52 patients diagnosed with CS in this study. Their clinical characteristics are presented in Table 1. Notably, this group consisted of 5 males and 47 females, with a mean age of 49.4 ± 15.8 years, median body mass index (BMI) of 23.0 [21.3–28.0] kg/m², and median UFC level of 272.1 [126.0–435.0] µg/day. Of the CS patients, 16 had CD and 36 had ACS, which is consistent with epidemiological data on CS observed in Asians (including Japanese individuals); however, this differed from epidemiological data from Western countries [35, 36]. Regarding comorbidities, 43 patients were diagnosed with hypertension—of which 34 were prescribed antihypertensive medications—with a mean systolic blood pressure (BP) of 136.4 ± 21.5 mmHg and diastolic BP of 83.5 ± 15.0 mmHg. In addition, 44 patients were diagnosed with glucose metabolism impairment—of which, 20 were prescribed oral hypoglycemic agents and/or insulin—with a median fasting serum glucose level of 99.5 [87.3–116.5] mg/dL and median HbA1c level of 6.3% [5.7–7.4]. Moreover, 29 patients were diagnosed with osteoporosis, of which 4 were prescribed antiosteoporosis medication, with BMD T-score SDs of -1.54 ± 1.39, -1.76 ± 1.12, and -0.50 [-1.53–0.50] for the lumber spine, femoral neck, and distal radius, respectively. Notably, the UFC levels were higher in patients with CD than in those with ACS (412.6 [243.2–1,100.3] vs. 215.3 [114.0–387.8] µg/day); however, there were no significant differences attributed to sex, age, BMI, or the proportion of patients with respect to comorbidities, including hypertension and glucose metabolism impairment, between patients with CD and ACS.

Table 1 Clinical characteristics of the patients

Full size table

The median duration from the patients’ initial recognition of CS-related manifestations to diagnosis was 44.0 [13.3–125.3] months, and it took more than 3 years to diagnose CS in 30 patients (58%). Furthermore, the median number of medical facilities visited by patients before diagnosis was 3.0 [2.0–5.0]; however, there were no significant differences in the duration or number of medical institutions between patients with CD and those with ACS.

Frequency and concordance between patient-reported and physician-assessed CS-related manifestations

Each manifestation reported by a patient or assessed by a physician is shown vertically for individual cases in Fig. 1. Compared with nonspecific features, typical features appeared to not be reported by the patients but were only assessed by the physicians. In addition, compared to nonspecific features, there were fewer cases in which the manifestations reported by the patients were consistent with those assessed by physicians for typical features.

Consistent with the impact of these visually distinctive presentations shown in Fig. 1, no correlation was observed in the number of typical features between patient-reported and physician-assessed manifestations (r = –0.20, P = 0.16) (Fig. 2A), whereas a positive correlation was found for nonspecific features (r = 0.62, P < 0.01) (Fig. 2B). Moreover, the total number of patient-reported manifestations of typical features was lower than that of physician-assessed manifestations (1.0 [0.0–2.0] vs. 3.5 [3.0–4.0], P < 0.01), and four of the five typical features were reported less frequently by patients than by physicians, except for proximal myopathy (Table 2A). According to Cohen’s kappa coefficient, the concordance between patient-reported and physician-assessed manifestations was marked as “Fair” to “Slight,” indicating a discrepancy for all typical features. Similarly, the total number of patient-reported manifestations of nonspecific features was also lower than that in physicians (2.5 [2.0–3.0] vs. 4.0 [3.0–5.0], P < 0.01). However, except for glucose metabolism impairment or osteoporosis, there were no differences in the frequencies of nonspecific features between patient-reported and physician-assessed manifestations, and the concordance of the nonspecific features between the patient-reported and physician-assessed manifestations was “Almost perfect” for menstrual abnormality and “Substantial” for mental abnormality and hypertension, whereas that for glucose metabolism impairment and osteoporosis was “Fair.” This suggests that the discrepancy between patient-reported and physician-assessed manifestations was more significant for typical than for nonspecific features. However, no differences in these discrepancies were observed between patients with CD and those with ACS (Table 2B, C).

Table 2 Frequencies of patient-reported and physician-assessed manifestations and their concordance. A. All patients (n = 52). B. Patients with CD (n = 16). C. Patients with ACS (n = 36)

Full size table

We performed logistic regression analyses using UFC to investigate whether excess cortisol levels influenced the discrepancy between patient-reported and physician-assessed manifestations. Notably, we observed no association between UFC levels and discrepancies between patient-reported and physician-assessed manifestations in the univariate or multivariate logistic regression analyses adjusted for sex and age (Table 3A). In addition, no association was observed after adjusting for other variables such as BMI and disease duration. Similarly, we found that the serum cortisol levels after the low-dose dexamethasone suppression test (LDDST) were not associated with discrepancies between patient-reported and physician-assessed manifestations (Table 3B). Thus, these disparities were shown to be insignificant when directly related to the severity of CS.

Table 3 Logistic regression analyses of the discrepancies between the patient-reported and physician-assessed manifestations. A. Variables associated with UFC levels. B. Variables associated with serum cortisol levels after the LDDST

Full size table

Discussion

In the present study, we highlight the challenges associated with the diagnosis of CS—a condition resulting from excessive glucocorticoid exposure—and elucidate the divergence between patient-reported and physician-assessed manifestations. Thus, this study may aid in the early detection of CS by identifying symptoms that patients are unable to recognize based on the disparities between patient-reported and physician-assessed manifestations of CS.

In this study, the number of patient-reported manifestations of both typical and nonspecific features was lower than that of physician-assessed manifestations, suggesting that CS symptoms may have been overlooked by relying solely on patient reports. Additionally, analysis of the concordance between patient-reported and physician-assessed manifestations revealed a tendency for these manifestations to be inconsistent for both typical and nonspecific features, with a tendency to be more significant for typical features. Furthermore, the UFC and serum cortisol levels after the LDDST, which represent the severity of CS, were not associated with the concordance of manifestations between patients and physicians, suggesting that even in cases of severe CS, patients may not recognize their symptoms. These findings imply that typical features, which are essential for diagnosing CS, may be difficult for patients to recognize and poorly identified or conveyed to patients by non-specialist physicians, who are typically the first to interact with individuals with CS. The importance of educating healthcare providers such as primary care physicians, family physicians and gynecologists for early diagnosis of CS should be highlighted.

According to a previous report on the diagnostic history of 176 patients with CD, 83% of the patients visited their family physician for manifestations such as weight gain and hypertension, while 46% visited a gynecologist for menstrual abnormalities before the diagnosis of CD [11]. Thus, the typical features of CS were not recognized. The examination may reveal nonspecific features. However, individuals who are non-specialists may not recognize these features as indications of CS. Therefore, patients are often unaware of the potential complications associated with CS. This is consistent with the results of our study, in which patient-reported and physician-assessed manifestations were more consistent for hypertension and menstrual abnormalities than for other manifestations such as typical features, glucose metabolism impairment, and osteoporosis. This makes diagnosis challenging as non-specialist physicians and, more prominently, patients may not recognize the full range of symptoms associated with CS, especially the typical features with high diagnostic value. In addition, older patients diagnosed with CS present with a lower BMI and waist circumference than younger patients [37], and they typically do not exhibit symptoms commonly associated with CS such as skin alterations, depression, hair loss, hirsutism, and reduced libido. These findings may further complicate the diagnosis of CS in elderly patients.

By evaluating only the patient-reported manifestations, it appears that manifestations such as peripheral edema and proximal myopathy were more common. Possibly, these symptoms were not considered features of CS by physicians, in comparison to the degree of symptoms experienced by the patients. However, this may not necessarily imply diminishing the significance of the patient’s signs and symptoms, as these manifestations can be considered as the unidentified complaints and may result in a postponement of the diagnosis of CS. Patients may be experiencing symptoms that physicians do not perceive, indicating the importance of interview and physical examination. Further investigation is needed to elucidate underlying factors.

Considering the rarity of CS, it is crucial to suspect and diagnose the condition based on clinical symptoms and perform the appropriate screening tests without over- or under-screening [7]. Although CS screening in patients with diabetes mellitus and hypertension has been reported to lead to a diagnosis in only 0–0.7% and 0.1–0.5% of these patients, respectively [38,39,40,41], it is ineffective in terms of false positives and cost [9]. Therefore, patients with typical features that are highly specific for CS, such as purple striae, easy bruising, and proximal myopathy [1, 8, 12], as well as those with obesity, diabetes mellitus, or hypertension in combination with these features, should be screened for CS [7, 27]. However, our results suggest that these symptoms are unlikely to be self-recognized. Therefore, the appropriate screening measures must be implemented to establish an early and effective diagnosis of CS.

In these situations, it is crucial for physicians to utilize their knowledge and experience to suspect CS based on symptoms such as typical features [10]. It has been reported that years of clinical experience in endocrine practice can contribute to the estimation of the pre-test probability of CS [16]. In contrast, non-specialists are less likely to encounter patients with CS in their lifetime, which can make it difficult to properly suspect CS [9]. From this perspective, it is of utmost importance that family physicians and general internists are knowledgeable regarding the manifestations that require screening for CS, as early diagnosis of this uncommon and severe condition is crucial [11]. Therefore, it is important for physicians who routinely treat patients presenting with common symptoms such as obesity, diabetes mellitus, and hypertension to meticulously interview and observe for any indicators of CS, even if the patient does not recognize them. Failure to adopt an appropriate tone in these situations may cause the disease to become undetectable.

In rare disorders such as CS, in addition to enhancing public recognition of the disease, the appropriate sharing of information and provision of specialized care in clinical practice remain important issues [42]. Early identification of such rare diseases can be achieved by promoting an understanding of the disease and its symptoms among family, friends, and patients who may be the first to recognize the signs and symptoms in an individual. In fact, in a questionnaire survey of 340 patients with CS across 30 countries, the diagnosis of CS was made in 5.6% of cases by the patients themselves and in 0.9% by their family or friends [43]. In the present study, we found that it took more than 3 years to diagnose CS in 58% of the cases. If CS and its symptoms are popularized among the public, the typical features of CS could be more readily reported to physicians and the time to diagnosis might be shorter. Furthermore, a primary care physician who is well-educated and knowledgeable is crucial in ensuring that the concerns of such individuals are not overlooked.

This study has some limitations. First, this single-center retrospective study included a relatively small sample size with few male patients. Second, CD and ACS have different pathologies; therefore, the frequencies of several CS-related manifestations will differ depending on their subtypes [3, 44]. However, in this study, there was no difference in the discrepancies between patient-reported and physician-assessed manifestations in patients with CD or ACS. Nonetheless, it is crucial that comprehensive research is conducted in larger patient populations with a focus on employing methods that accurately reflect the pathophysiology of CD and ACS. Third, patient reports may be inaccurate in terms of onset and duration because they depend on the patient’s memory. Fourth, the endocrinologists who examined the patients differed, which may have affected the presence or absence of physician-assessed manifestations. Finally, this study investigated the differences between the manifestations reported by patients and those assessed by endocrinologists, although the evaluations conducted by primary care physicians, which are crucial for the early detection of CS, were not available. Future research is needed to investigate the differences in recognizing manifestations between non-specialist physicians and endocrinologists with extensive experience in CS and to examine the changes before and after education for these non-specialists to determine if they can lead to earlier diagnosis of CS.

In conclusion, endocrinologists have been shown to be aware of CS-related symptoms, especially typical features, whereas patients do not recognize these manifestations, even when the disease is severe. Therefore, the key to the early diagnosis and treatment of CS is a more proactive approach of questioning and examining patients suspected of having the disease.

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Acknowledgements

We thank all the physicians and medical assistants who were involved in this study. We are grateful to all the laboratory members for their excellent discussions and fruitful suggestions. We also thank Editage (www.editage.jp) for English language editing.

Funding

This work was partially supported by the Japan Society for the Promotion of Science (KAKENHI, grant numbers 22K08654 (HF) and 21K08555 (GI)) and the Hyogo Science and Technology Association (HF). Open Access funding provided by Kobe University.
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Author notes
1. These authors contributed equally: Yuma Motomura, Shin Urai
Authors and Affiliations
1. Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan
  
  Yuma Motomura, Shin Urai, Masaaki Yamamoto, Masaki Suzuki, Naoki Yamamoto, Genzo Iguchi & Wataru Ogawa
2. Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Hospital, Kobe, Hyogo, 650-0017, Japan
  
  Hironori Bando & Hidenori Fukuoka
3. Medical Center for Student Health, Kobe University, Kobe, Hyogo, 657-8501, Japan
  
  Genzo Iguchi
4. Department of Biosignal Pathophysiology, Kobe University Graduate School of Medicine, Kobe, Hyogo, 657-8501, Japan
  
  Genzo Iguchi
Contributions

Conceptualization and methodology: Y.M., S.U., G.I., and H.F.; Data curation and investigation: Y.M. and S.U.; Resources: Y.M., S.U., M.Y., M.S., N.Y., and H.F.; Formal analysis: Y.M. and S.U.; Writing – original draft preparation and visualization: Y.M. and S.U.; Writing – review and editing: H.B., M.Y., M.S., N.Y., G.I., W.O., and H.F.; Project administration and supervision: H.F. All the authors contributed to the discussion and approved the final version of the manuscript.

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Correspondence to Hidenori Fukuoka.
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This study conformed to the Declaration of Helsinki guidelines and was approved by the Ethics Committee of Kobe University Hospital (Approval No. 1351).

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Informed consent was obtained from all the participants using an opt-out approach.

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Motomura, Y., Urai, S., Bando, H. et al. Diagnostic dilemma in Cushing’s syndrome: discrepancy between patient-reported and physician-assessed manifestations. Endocrine (2024). https://doi.org/10.1007/s12020-024-03935-9

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Received29 April 2024

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Published25 June 2024

DOI https://doi.org/10.1007/s12020-024-03935-9

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Meta

Introduction

Methods

Clinical presentation of CS in children

Diagnostic workup for CS

Screening for endogenous hypercortisolism

24-h Urinary free cortisol (UFC)

Late night cortisol

Low-dose dexamethasone suppression tests (DST)

Etiological diagnosis of endogenous CS

Basal electrolytes and ACTH

CRH stimulation test

Desmopressin test

Standard high dose dexamethasone suppression test (HDDST)

Imaging

Pituitary magnetic resonance imaging (MRI)

Bilateral petrosal sinus sampling (BIPSS)

Radiological anatomic imaging

Functional imaging

Algorithm approach

Conclusions

Declarations

Ethical approval

Informed consent

Conflict of interest

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Abstract

Summary

Learning points

Background

Case presentation

Investigation

Treatment

Outcome and follow-up

Discussion

Declaration of interest

Funding

Patient consent

Author contribution statement

Acknowledgements

References

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Abstract

Background

Methods

Results

Conclusions

Methods

Research team background and epistemological underpinnings

Participants

Procedure

Analysis

Results

Lack of patient-centered care

Patient misunderstanding of symptoms

Experienced weight stigma

Diagnosis as a golden ticket

Discussion

Limitations

Conclusion

Data availability

References

Acknowledgements

Funding

Author information

Authors and Affiliations

Contributions

Corresponding author

Ethics declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Additional information

Publisher’s note