adrenal Cushing’s | CushieBlog

Cushing’s Syndrome Subtype Affects Postoperative Time to Adrenal Recovery

Posted on January 25, 2026 by MaryO

Berr CM. J Clin Endocrinol Metab. 2014;doi:10.1210/jc.2014-3632.

January 16, 2015

In patients undergoing curative surgical tumor resection for Cushing’s syndrome, the time to recovery of adrenal function is contingent upon the underlying etiology of the disease, according to recent findings.

In the retrospective study, researchers reviewed case records of 230 patients with Cushing’s syndrome. All patients were seen at a tertiary care center in Munich between 1983 and 2014, whose cases were documented in the German Cushing’s Registry. Patients were divided into three subgroups of Cushing’s syndrome: Cushing’s disease, adrenal Cushing’s syndrome and ectopic Cushing’s syndrome.

After applying various exclusion criteria, the researchers identified 91 patients of the three subgroups who were undergoing curative surgery at the hospital. The patients were followed for a median of 6 years. The researchers defined adrenal insufficiency as the need for hydrocortisone replacement therapy, and collected this information from patient records and laboratory results.

The duration of adrenal insufficiency was calculated as the interval between successful surgery and the completion of hydrocortisone replacement therapy. Cushing’s syndrome recurrence was defined as biochemical and clinical signs of hypercortisolism.

The researchers found a significant difference between Cushing’s syndrome subtypes in the likelihood of regaining adrenal function within 5 years of follow-up: The probability was 82% in ectopic Cushing’s syndrome, 58% in Cushing’s disease and 38% in adrenal Cushing’s syndrome (P=.001). Among the 52 participants who recovered adrenal function, the median type to recovery also differed between subtypes and was 0.6 years in ectopic Cushing’s syndrome, 1.4 years in Cushing’s disease and 2.5 years in adrenal Cushing’s syndrome (P=.002).

An association also was found between younger age and adrenal recovery in the Cushing’s disease participants (P=.012).

This association was independent of sex, BMI, symptom duration, basal adrenocorticotropic hormone and cortisol levels. No association was seen between adrenal recovery and length of hypercortisolism or postoperative glucocorticoid replacement dosage.

“It is the main finding of this series that the median duration of tertiary adrenal insufficiency was dependent on the etiology of [Cushing’s syndrome]: It was shortest in the ectopic [Cushing’s syndrome], intermediate in [Cushing’s disease] and longest in adrenal [Cushing’s syndrome] caused by unilateral cortisol producing adenoma,” the researchers wrote. “The significant difference to [Cushing’s disease] is an unexpected finding since by biochemical means cortisol excess is generally less severe in adrenal [Cushing’s syndrome]. If confirmed by others, our data have clinical impact for the follow-up of patients after curative surgery: Patients should be informed that adrenocortical function may remain impaired in benign conditions such as cortisol-producing adenoma.”

Disclosure: The study was funded in part by the Else Kröner-Fresenius Stiftung.

The original article is here: Healio

Filed under: adrenal, adrenal crisis, Cushing's, pituitary | Tagged: adenoma, adrenal Cushing's, adrenal insufficiency, cortisol, Cushing's Disease, Cushing's Syndrome, ectopic, hypercortisolism, pituitary, tumor | Leave a comment »

Cushing’s Syndrome Etiology Affects Adrenal Function Recovery

Posted on January 21, 2026 by MaryO

Abstract

Context:

Successful tumor resection in endogenous Cushing’s syndrome (CS) results in tertiary adrenal insufficiency requiring hydrocortisone replacement therapy.

Objective:

The aim was to analyze the postsurgical duration of adrenal insufficiency of patients with Cushing’s disease (CD), adrenal CS and ectopic CS.

Design:

We performed a retrospective analysis based on the case records of 230 CS patients in our tertiary referral center treated from 1983 to 2014. The mean follow-up time was 8 years.

Patients:

We included 91 patients of the three subtypes of CS undergoing curative intended surgery and documented follow-up after excluding cases with persistent disease, pituitary radiation, concurrent adrenostatic or somatostatin analogue treatment, and malignant adrenal disease.

Results:

The probability of recovering adrenal function within a 5 years follow-up differed significantly between subtypes (p=0.001). It was 82 % in ectopic CS, 58 % in Cushing’s disease and 38 % in adrenal CS. In the total cohort with restored adrenal function (n=52) the median time to recovery differed between subtypes: 0.6 (IQR 0.03–1.1) years in ectopic CS, 1.4 (IQR 0.9–3.4) years in CD, and 2.5 (IQR 1.6–5.4) years in adrenal CS (p=0.002). In CD the Cox proportional-hazards model showed that the probability of recovery was associated with younger age (hazard ratio 0.896, 95% CI 0.822–0.976, p=0.012), independently of sex, BMI, duration of symptoms, and basal ACTH and cortisol levels. There was no correlation with length and extend of hypercortisolism or postoperative glucocorticoid replacement doses.

Conclusions:

Time to recovery of adrenal function is dependent on the underlying etiology of CS.

Affiliations

¹Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Germany;
²Institut für Klinische Radiologie, Klinikum der Ludwig-Maximilians-Universität München, Germany;
³Chirurgische Klinik und Poliklinik – Innenstadt, Klinikum der Ludwig-Maximilians-Universität München, Germany;
⁴Klinik für Neurochirurgie, Klinikum Grosshadern, Ludwig-Maximilians-Universität München, Germany;
⁵IMSE, Klinikum rechts der Isar der TU München, München, Germany

From http://press.endocrine.org/doi/abs/10.1210/jc.2014-3632

Filed under: adrenal, adrenal crisis, Cushing's, pituitary | Tagged: abstract, adrenal Cushing's, adrenal insufficiency, Cushing's Syndrome, ectopic, hypercortisolism, surgery | Leave a comment »

Adrenal Cushing’s Syndrome in Pregnancy Complicated by Fetal Growth Restriction Following Retroperitoneoscopic Adrenalectomy

Posted on December 7, 2025 by MaryO

Abstract

A 29-year-old Japanese pregnant woman, G5P3A1, conceived spontaneously and was referred to our hospital because of uncontrolled hypertension at 24 weeks of gestation. On admission, she presented with physical findings characteristic of Cushing’s syndrome (CS), such as moon face, buffalo hump, and reddish-purple striae. Laboratory examination revealed hyperglycemia and hypercortisolism with suppressed adrenocorticotropic hormone levels. Imaging studies revealed a right adrenocortical adenoma, and the patient was clinically diagnosed with adrenal CS. At 28 weeks, she underwent retroperitoneoscopic adrenalectomy, which normalized maternal cortisol levels and improved metabolic abnormalities. Despite these improvements, she was diagnosed with fetal growth restriction accompanied by superimposed preeclampsia at approximately 33 weeks. The maternal serum soluble fms-like kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio was markedly elevated. At 36 weeks, an emergency cesarean section was performed for fetal compromise, resulting in the delivery of a small-for-gestational-age infant. Histopathological examination of the placenta revealed ischemic changes consistent with placental insufficiency. Both the mother and infant were discharged in stable conditions. The present case shows that although adrenalectomy during pregnancy can correct endocrine abnormalities, it does not necessarily prevent subsequent fetal growth restriction.

Introduction

Cushing’s syndrome (CS) is an endocrine disorder caused by chronic hypercortisolism. Because cortisol can disrupt ovulation, leading to menstrual irregularities and infertility [1,2], pregnancy in women with CS is exceedingly rare. Moreover, diagnosis during pregnancy is particularly challenging as many hallmark features of hypercortisolism – fatigue, weight gain, acne, and mood instability – are common in normal pregnancies.

Untreated CS during gestation is associated with substantially increased maternal and perinatal morbidity and mortality. Aggressive management during gestation, including cortisol synthesis inhibitors or surgical resection of pituitary adenomas or adrenal tumors, has been shown to improve maternal and fetal outcomes [3-5]. However, intensive treatment may not fully reduce the risks of fetal growth restriction and preterm delivery [5,6], and the underlying reason for this remains unclear.

Herein, we report a case of adrenal CS in a pregnant woman who underwent retroperitoneoscopic adrenalectomy at 28 weeks of gestation. Despite achieving biochemical remission of hypercortisolism after surgery, she developed fetal growth restriction and required preterm cesarean delivery due to fetal compromise.

This article was previously presented as a meeting abstract at (1) the 97th Annual Congress of the JES on June 7, 2024; (2) the 60th Annual Congress of JSPNM on July 15, 2024; and (3) the 47th Annual Meeting of JSGOS on November 24, 2024.

Case Presentation

A 29-year-old Japanese woman with a G5P3A1 conceived spontaneously. She had no medical history other than asthma and no particular familial history. She began receiving antenatal care at a nearby facility during the first trimester. She did not undergo screening tests for predicting the development of preeclampsia (PE), such as the first-trimester ultrasound at 11-14 weeks or pregnancy-associated plasma protein A assessment. Her casual blood glucose level was 87 mg/dL at 10⁺⁶ weeks of gestation. Initially, she was normotensive, but her blood pressure gradually increased to 144/100 mmHg at 18 weeks of gestation, and diagnosed as having chronic hypertension. Thereafter, her hypertension worsened, reaching 177/100 mmHg at 21 weeks of gestation, and she was diagnosed with superimposed PE. Around the same time, her body weight increased by 11.5 kg from the pre-pregnancy weight (from 58.5 kg to 70 kg), and generalized edema developed. As a result, she was admitted to the referring hospital and started taking antihypertensive treatment with oral methyldopa 750 mg/day, which lowered her blood pressure to a range of 130-150/80-100 mmHg, decreased her body weight to 66.5 kg, and improved the generalized edema. Although she was discharged from the hospital, her blood pressure increased again; thus, she was transferred to our institution, a tertiary referral perinatal medical center, at 24⁺⁶ weeks of gestation for subsequent perinatal management.

At her initial visit, her height and body weight were 153 cm and 66.2 kg, respectively. Her vital signs were as follows: body temperature 36.0℃, blood pressure 159/115 mmHg with the use of antihypertensive medication, and heart rate 80/min. She had an obvious full-moon face, acne vulgaris (Figure 1A), a buffalo hump, and reddish-purple striae on her abdomen and thighs (Figures 1B, 1C). She also had bilateral pitting edema in her lower legs and thin skin on the backs of her hands. No anemic palpebral conjunctiva, cervical lymphadenopathy, or thyroid enlargement was observed.

Figure 1: Macroscopic findings characteristic of Cushing’s syndrome

(A) Moon face, (B) reddish-purple striae

on abdomen, and (C) reddish-purple striae on thighs.

An increased neutrophil count and decreased eosinophil count were observed, although the white blood cell count was within the normal range (Table 1). Biochemical analysis showed that the serum potassium level was decreased (2.3 mEq/L). The serum total protein, albumin, blood urea nitrogen, and cholinesterase levels were mildly decreased. Renal function, hepatic function, and lipid profiles were within normal limits, except for elevated triglyceride levels. A spot urine test indicated an elevated urine protein-to-creatinine ratio (0.436 g/gCr) (Table 2). Regarding diabetes-related tests, fasting plasma glucose (91 mg/dL), glycated hemoglobin (HbA1c) (5.4%), and glycated albumin (GA) (12.9%) were all within their normal ranges. The serum C-peptide level was elevated. A 75 g oral glucose tolerance test (OGTT) conducted at 25⁺⁴ weeks of gestation showed serum glucose levels of 191 mg/dL at one hour and 212 mg/dL at two hours (Table 2), indicating postprandial hyperglycemia. Endocrinological evaluation revealed elevated morning serum cortisol levels with loss of diurnal variation. This hypercortisolism is accompanied by suppressed plasma adrenocorticotropic hormone (ACTH) levels (Table 3). The 24-hour urinary free cortisol (UFC) level was markedly elevated (1,380 μg/day). In contrast, dehydroepiandrosterone sulfate (DHEA-S) levels decreased. Serum thyroid-stimulating hormone (TSH) was markedly decreased (0.091 IU/mL), accompanied by mild reductions in free T3 (1.65 pg/mL) and free T4 (0.65 ng/dL), which indicated central hypothyroidism. Abdominal ultrasonography revealed a nodule in the right adrenal gland with a maximum diameter of approximately 30 mm (28 × 27 × 25 mm) (Figure 2A). Abdominal magnetic resonance imaging (MRI) detected a 27-mm well-defined nodular lesion at the same location, which demonstrated a signal drop on opposed-phase images (Figure 2B). Obstetric ultrasonography revealed an estimated fetal body weight of 742 g (adequate for gestational age) (Figures 3A–3C), an amniotic fluid index of 16.4 cm (Figure 3D), and no major structural anomalies of the fetus. From the day of referral, oral nifedipine (40 mg/day) was initiated as antihypertensive therapy. Potassium chloride (KCl) was administered orally.

Parameter	Test value	Reference range
CBC
WBC	8.1×10⁹/L	3.3-8.6 ×10⁹/L
Neut	83.5%	38.5-80.5%
Lymph	10.5%	16.5-49.5%
Mono	5.8%	2.0-10%
Eosino	0.1%	0.0-8.5%
RBC	3.17×10¹²/L	3.86-4.92 ×10¹²/L
Hb	11.5 g/dL	11.4-16.8 g/dL
Plt	190×10⁹/L	158-348 ×10⁹/L
Serum Biochemistry
TP	5.7 g/dL	6.6-8.1 g/dL
Alb	3.3 g/dL	4.1-5.1 g/dL
T-Bil	1 mg/dL	0.4-1.5 mg/dL
AST	15 U/L	13-30 U/L
ALT	27 U/L	7-23 U/L
LDH	326 U/L	124-222 U/L
ALP	55 U/L	38-113 U/L
γ-GTP	29 U/L	9-32 U/L
Na	146 mEq/L	138-145 mEq/L
K	2.3 mEq/L	3.6-4.8 mEq/L
Cl	107 mEq/L	101-108 mEq/L
Ca	8.5 mg/dL	8.8-10.1 mg/dL
P	2.1 mg/dL	2.7-4.6 mg/dL
BUN	6 mg/dL	8-20 mg/dL
UA	3.4 mg/dL	2.6-5.5 mg/dL
Cr	0.45 mg/dL	0.46-0.79 mg/dL
CRP	0.1 mg/dL	0-0.14 mg/dL
HDL-C	66 mg/dL	48-103 mg/dL
LDL-C	134 mg/dL	65-163 mg/dL
TG	211 mg/dL	30-117 mg/dL
FPG	91 mg/dL	73-109 mg/dL
HbA1c	5.4%	4.9-6.0%
GA	12.9%	12.3-16.5%
C-peptide	3.7 ng/mL	0.6-1.8 ng/mL
Endocrinology
Adrenaline	<0.01 ng/mL	<0.17 ng/mL
Noradrenaline	0.09 ng/mL	0.15-0.57 ng/mL
Dopamine	<0.02 ng/mL	<0.03 ng/mL
Cortisol	24.7 μg/dL	3.7-19.4 μg/dL
Aldosterone	<4.0 pg/mL	4.0-82.1 pg/mL
Renin activity	0.7 ng/mL/hr	0.2-3.9 ng/mL/hr
DHEA-S	43 μg/dL	92-399 μg/dL
TSH	0.091 IU/mL	0.350-4.940 IU/mL
FT3	1.65 pg/mL	1.68-3.67 pg/mL
FT4	0.65 ng/dL	0.70-1.48 ng/dL

Table 1: Laboratory data of CBC, serum biochemistry, and endocrinology

CBC: complete blood count, WBC: white blood cell count, Neut: neutrophil, Lymph: lymphocyte, Mono: monocyte, Eosino: eosinophil, RBC: red blood cell count, Hb: hemoglobin, Plt: platelet count, TP: total protein, Alb: albumin, T-Bil: total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: gamma-glutamyl transpeptidase, Na: sodium, K: potassium, Cl: chloride, Ca: calcium, P: phosphorus, BUN: blood urea nitrogen, UA: uric acid, Cr: creatinine, CRP: C-reactive protein, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, TG: triglyceride, FPG: fasting plasma glucose, HbA1c: hemoglobin A1c, GA: glycated albumin, C-peptide: connecting peptide, DHEA-S: dehydroepiandrosterone sulfate, TSH: thyroid-stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine

Parameter	Test value
75-g OGTT
PG
0 min	91 mg/dL
30 min	153 mg/dL
60 min	191 mg/dL
90 min	204 mg/dL
120 min	225 mg/dL
IRI
0 min	10.8 μU/mL
30 min	29.3 μU/mL
60 min	48.7 μU/mL
90 min	64.6 μU/mL
120 min	91.2 μU/mL
Urinalysis
U-Cr	39 mg/dL
U-TP	17 mg/dL
U-TP/Cr	0.436 g/gCr

Table 2: Laboratory data of 75-g OGTT and urinalysis

OGTT: oral glucose tolerance test, PG: plasma glucose, IRI: immunoreactive insulin, U-Cr: urinary creatinine, U-TP: urinary total protein

Parameter	Test value	Reference range
ACTH/F diurnal rhythm
ACTH
6:00 AM	2.1 pg/mL	7.2-63.3 pg/mL
4:00 PM	2.0 pg/mL	7.2-63.3 pg/mL
11:00 PM	2.3 pg/mL	7.2-63.3 pg/mL
F
6:00 AM	24.7 μg/dL	3.7-19.4 μg/dL
4:00 PM	25 μg/dL	3.7-19.4 μg/dL
11:00 PM	25.8 μg/dL	3.7-19.4 μg/dL

Table 3: Laboratory data of ACTH/F diurnal rhythm

ACTH: adrenocorticotropic hormone, F: cortisol

Figure 2: Radiological findings of the right adrenal tumor (white arrow)

(A) Trans-abdominal ultrasonography image and (B) coronal section of the trunk on MRI.

Figure 3: Obstetric ultrasonography

(A) The plane used for biparietal diameter measurement, (B) the plane used for abdominal circumference measurement, (C) the plane used for femoral length measurement, and (D) the plane used for amniotic fluid index measurement.

Physical examination revealed typical signs of CS, such as a moon face, buffalo hump, and reddish-purple striae. In addition, laboratory findings showed elevated UFC, increased nocturnal serum cortisol levels (>5.0 μg/dL), and suppressed ACTH levels (<5.0 pg/mL). On the basis of these findings, the patient was diagnosed with ACTH-independent CS. Furthermore, imaging studies identified a right adrenal mass, leading to a final diagnosis of CS caused by a right adrenal tumor. Both central hypothyroidism and impaired glucose tolerance were considered secondary complications, primarily caused by hypercortisolemia due to CS. The serum potassium level was maintained at approximately 3.0 mEq/L after the administration of oral KCl. An increase in the nifedipine dose from 20 mg/day to 40 mg/day stabilized the blood pressure at approximately 140/90 mmHg (Figure 4A). Intensive insulin therapy with insulin lispro was initiated on hospital day 4 (Figure 4B), and the insulin dosage was gradually increased for postprandial hyperglycemia. The maximum insulin dose was 41 units/day on day 23 of hospitalization. Throughout this period, the UFC levels remained persistently elevated (Figure 4C).

Figure 4: Clinical course between hospitalization and cesarean delivery

(A) Blood pressure trend, (B) total dose of insulin, and (C) urinary free cortisol trend.

A clinical team of obstetricians, urologists, and endocrinologists discussed the treatment plans for CS and perinatal management. Pharmacological treatment had two problems: radicality and risk of fetal adrenal insufficiency due to placental passage of medication; therefore, we decided to perform adrenalectomy during pregnancy. At 28⁺³ weeks of gestation, a retroperitoneoscopic adrenalectomy was performed by urologists. After the induction of general anesthesia, the patient lay on the bed in a complete left lateral position (Figures 5A, 5B). Consequently, the endoscope and instrument ports were placed in the same configuration as those used in the conventional retroperitoneal approach for nonpregnant patients. Port placements were planned guided by abdominal ultrasonography to identify the uterine position, and the assistant port was positioned at a location that minimized potential interference with the uterus. The surgery was completed without complications. The operative time was 83 minutes, and bleeding was minimal. Histopathological examination indicated that the tumor was an adrenocortical adenoma (Figures 6A–6C).

Figure 5: Photograph showing the patient in the left lateral decubitus position after general anethesia

(A) Abdominal area and (B) dorsal area.

Figure 6: Histopathological findings of the right adrenal gland (A, B, C) and placenta (D)

(A) Macroscopic view of the right adrenal gland showing the normal adrenal tissue (black asterisk) and the adrenal tumor (white asterisk). (B, C) Microscopic findings of the right adrenal gland and tumor (H&E staining).

(B) Normal adrenal gland (black asterisk) and adrenal tumor (white asterisk) separated by a thin fibrous capsule (black arrow).

(D) Microscopic findings of the placenta (H&E staining) showing fibrin deposition within villous vessels (black arrow) and chorionic villi with loss of nuclear detail and crowding (black asterisk).

After surgery, the maternal glucose tolerance rapidly improved, and intensive insulin therapy with insulin lispro became unnecessary (Figure 4B). To avoid postoperative adrenal insufficiency, replacement therapy with hydrocortisone was initiated at 200 mg/day immediately after surgery, and the dosage was gradually tapered to 25 mg/day before delivery (Figure 4C). Maternal thyroid function normalized two weeks after surgery. At 29 weeks of gestation, oral nifedipine (40 mg/day) was stopped and blood pressure was monitored; however, high blood pressure was sustained. Therefore, oral nifedipine was resumed at 20 mg/day at 31 weeks of gestation. At approximately 33 weeks of gestation, the fetus exhibited slow growth, leading to a diagnosis of fetal growth restriction. The levels of serum soluble fms-like kinase 1 (sFlt-1)/placental growth factor (PlGF) were 173 (7990/46.1) at 33⁺⁰, 299 (11600/38.9) at 34⁺¹, and 316 (15200/48.1) at 35⁺⁵ weeks. Trends in the estimated fetal body weight and standard deviation are shown in Figure 7. At 36⁺¹ weeks of gestation, cardiotocography revealed severely prolonged deceleration regardless of the absence of uterine contraction, and an emergency cesarean section was performed. A male infant weighing 1,726 g and 41 cm in height, diagnosed as small for gestational age, was born with Apgar scores of 8 at one minute and 9 at five minutes. The umbilical arterial pH was 7.36. The size and weight of the placenta were 14.7 × 12.8 × 3.0 cm and 315 g, respectively, and histopathological examination revealed findings consistent with ischemic infarction (Figure 6D). Antihypertensive drugs administered to the mother were discontinued on day 8. The mother and neonate were discharged on POD 20. The child achieved normal development at the age of two years.

Figure 7: Trends in estimated fetal body weight (EFBW) and standard deviation (SD)

Discussion

This case illustrates adrenal CS in pregnancy, complicated by the subsequent development of fetal growth restriction, despite retroperitoneoscopic adrenalectomy at 28 weeks of gestation. Notably, a markedly increased maternal serum sFlt-1/PlGF ratio was detected at the time of diagnosis of fetal growth restriction. To the best of our knowledge, this is the first case in which angiogenic markers were evaluated in a pregnant woman with adrenal CS.

The coexistence of CS and pregnancy is extremely rare [4]. The primary reason for this rarity is infertility, often caused by the hypercortisolism characteristic of CS. Specifically, hypercortisolism suppresses the hypothalamic-pituitary-gonadal axis, leading to impaired follicular development and anovulation by disrupting the secretion of gonadotropin-releasing hormone (GnRH) [1,7]. Pregnancy poses significant challenges in patients with ACTH-dependent CS, in whom excessive ACTH production is accompanied by androgen overproduction. As a result, adrenal etiologies of CS are more common than pituitary-dependent etiologies during pregnancy [3]. Several factors make it difficult to diagnose CS during pregnancy. First, the characteristic physical findings of CS closely mimic physiological changes in normal pregnancy. For example, weight gain, abdominal striae, and edema are common symptoms of both conditions. Therefore, this overlap can cause delayed diagnosis or misdiagnosis of CS during pregnancy [3]. It has been reported that 21.5% of pregnant women with CS are diagnosed only after delivery [3]. Second, physiological hormonal changes during pregnancy complicate the diagnostic process. During gestation, the placenta produces corticotropin-releasing hormone (CRH) and ACTH [8]. Additionally, elevated estrogen levels increase the synthesis of corticosteroid-binding globulin, resulting in a state of physiological hypercortisolism in pregnant women [9,10]. Consequently, the dexamethasone suppression test, which is key to the diagnosis of CS, is often unreliable in pregnant women because of the high incidence of false-positive results [4].

Despite these diagnostic hurdles, certain findings are highly valuable in identifying CS during pregnancy. First, careful examination of physical signs specific to CS, such as skin thinning and the presence of wide, reddish-purple striae, is crucial. Second, the evaluation of diurnal cortisol rhythms was informative. While this rhythm is preserved in normal pregnancy, it is characteristically absent in CS. Therefore, measuring late-night serum cortisol levels is useful for differentiating between these two states [11]. Third, a 24-hour UFC level exceeding three times the upper limit of normal for non-pregnant individuals is strongly suggestive of CS [4,7,9]. In the present case, these key features were decisive for the diagnosis. We found wide, reddish-purple striae, a loss of diurnal cortisol rhythm, and a markedly elevated 24-hour UFC level. Based on these findings, we definitively diagnosed the patient with CS complicating pregnancy.

According to a systematic review of 263 pregnancies complicated by CS, untreated pregnant women were significantly more likely to develop PE than those treated beforehand (26.5% vs. 2.3%) [3]. PE is characterized by defective placentation and impaired spiral artery remodeling, leading to placental ischemia during early pregnancy. Placental ischemia produces sFlt-1, a splice variant of Flt-1 that binds to vascular endothelial growth factor and PlGF and serves as a biochemical marker of endothelial dysfunction that inhibits angiogenesis [12]. Systemic endothelial dysfunction leads to maternal hypertension, proteinuria, and damage to other organs, including the placenta. In this case, placental histopathology indicated ischemic changes without retroplacental hematoma. In addition, a marked elevation of the sFlt-1/PlGF ratio – resulting from both increased sFlt-1 and decreased PlGF – was detected, supporting the presence of placental ischemia due to impaired placentation in early pregnancy.

In this case, several factors may have contributed to the placental ischemia. First, poor control of maternal hyperglycemia or hypertension may have played a role. As hyperglycemia is known to induce oxidative stress [13], it is possible that hyperglycemia in early pregnancy causes placental ischemia indirectly via oxidative stress. Recent studies suggest that hypertension in early pregnancy may contribute to impaired placentation, thereby increasing the risk of subsequent superimposed PE [14,15]. Therefore, chronic hypertension associated with CS may also be related to placental ischemia, although the maternal outpatient blood pressure was within the normal range during early pregnancy in the present case. Second, chronic hypercortisolemia can directly contribute to abnormal placentation. Previous animal experiments have shown that elevated maternal serum cortisol levels enhance uterine arterial contractions [16], which may induce placental ischemia. Furthermore, chronic hypercortisolism may exceed the protective capacity of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which shields the fetus from excessive cortisol, thereby directly affecting the fetus [17]. Based on these findings, it is presumed that irreversible placental damage had already occurred at the time of the surgical resection in this case. Preconceptional or at least early diagnosis and treatment of CS are crucial for preventing fetal growth restriction associated with superimposed PE after surgery.

The second trimester is generally considered the optimal period for adrenalectomy in pregnant patients with adrenal CS [18]; however, successful procedures have been reported even during the third trimester [6,19]. Endoscopic adrenalectomy is favored over open approaches owing to its reduced morbidity, although direct comparisons between the transperitoneal and retroperitoneal approaches in pregnancy are lacking. In non-pregnant patients, both approaches yield similar operative times, blood loss, and hospital stays [20]. In this case, the retroperitoneal approach was used. This technique offers several advantages during pregnancy as follows: it allows surgery in the lateral position, minimizes inferior vena cava compression by the gravid uterus, avoids entry into the peritoneal cavity, thereby preventing interference from the enlarged uterus, and reduces the risk of intra-abdominal inflammatory spread to the uterus and adjacent organs. Based on our experience and considering the potential advantages of the retroperitoneoscopic approach, we propose that retroperitoneoscopic adrenalectomy should be considered even in the early third trimester, as it may safely prolong gestation and reduce the need for preterm delivery.

Conclusions

This case highlights the challenges of managing adrenal CS during pregnancy. Uncontrolled CS may impair placental development during early pregnancy; therefore, preconceptional or at least early recognition and appropriate management are crucial to minimize the risk of subsequent fetal growth restriction. Further research is needed to clarify the pathophysiological relationship between hypercortisolism and impaired placentation in early pregnancy and to refine strategies for managing this rare but high-risk condition.

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Diagnostic dilemma in Cushing’s syndrome: discrepancy between patient-reported and physician-assessed manifestations

Posted on July 31, 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 [13‐15]; 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 [19‐21]. 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 [22‐24]. 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 [28‐30]. 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

	Total	CD	ACS	CD vs. ACS P value
Number of men/women	5/47	1/15	4/32	1.00
Age (years)	49.4 ± 15.8	54.3 ± 19.2	47.2 ± 13.8	0.14
BMI (kg/m²)	23.0 [21.3–28.0]	24.7 [22.2–30.0]	22.8 [20.8–26.4]	0.17
Midnight F (µg/dL)	20.1 [16.0–23.5]	20.2 [13.9–24.7]	20.1 [16.9–23.0]	0.97
F after LDDST (μg/dL)	21.2 ± 6.9	24.2 ± 10.1	19.7 ± 4.2	0.11
UFC (μg/day)	272.1 [126.0–435.0]	412.6 [243.2–1,100.3]	215.3 [114.0–387.8]	0.02
Basal ACTH (pg/mL)	2.0 [0.0–53.9]	83.2 [57.4–169.9]	0.0 [0.0–2.1]	<0.01
Systolic BP (mmHg)	136.4 ± 21.5	140.5 ± 20.7	134.6 ± 21.8	0.36
Diastolic BP (mmHg)	83.5 ± 15.0	83.1 ± 14.3	83.6 ± 15.5	0.90
Use of antihypertensive drugs, n (%)	34 (65)	13 (81)	21 (58)	0.13
FSG (mg/dL)	99.5 [87.3–116.5]	110.0 [102.0–142.8]	92.5 [83.3–114.3]	0.01
HbA1c (%)	6.3 [5.7–7.4]	6.8 [5.9–8.6]	6.0 [5.7–7.1]	0.08
Use of OHA and/or insulin, n (%)	20 (38)	9 (56)	11 (31)	0.12
LS BMD T-score (SD)	−1.54 ± 1.39	−1.00 ± 1.38	−1.79 ± 1.35	0.07
LS BMD Z-score (SD)	−0.78 ± 1.37	0.13 ± 1.11	−1.20 ± 1.28	<0.01
FN BMD T-score (SD)	−1.76 ± 1.12	−1.73 ± 1.54	−1.78 ± 0.88	0.92
FN BMD Z-score (SD)	−0.79 ± 1.01	−0.39 ± 1.10	−0.99 ± 0.92	0.10
Radius BMD T-score (SD)	−0.50 [−1.53–0.50]	−0.30 [−2.50–0.40]	−0.60 [−1.30–0.60]	0.79
Radius BMD Z-score (SD)	0.60 [−0.60–1.50]	1.50[−0.60–1.80]	0.50[−0.50–1.00]	0.33
Use of antiosteoporosis drugs, n (%)	4 (8)	1 (6)	3 (8)	1.00
Time to diagnosis (months)	44.0 [13.3–125.3]	43.0 [15.0–128.3]	47.5 [12.5–125.3]	0.87
Number of medical institutions before diagnosis	3.0 [2.0–5.0]	3.0 [2.0–5.0]	3.0 [3.0–5.8]	0.23

The results are presented as mean ± SD for normally distributed data and median [interquartile range] for non-normally distributed data

CD Cushing’s disease, ACS adrenal Cushing’s syndrome, BMI body mass index, F cortisol, LDDST low-dose dexamethasone suppression test, UFC urinary free cortisol, ACTH adrenocorticotropic hormone, BP blood pressure, FSG fasting serum glucose, HbA1c hemoglobin A1c, OHA oral hypoglycemic agents, BMD bone mineral density, LS lumber spine, FN femoral neck

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.

Fig. 1

Consistency between patient-reported and physician-assessed manifestations for each individual case. The consistencies or discrepancies between patient-reported and physician-assessed manifestations are shown. Vertical lines represent manifestations in individual patients. CD Cushing’s disease, ACS adrenal Cushing’s syndrome

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).

Fig. 2

Correlation between the total number of patient-reported and physician-assessed manifestations. Correlations between the total number of patient-reported and physician-assessed manifestations are shown for typical (A) and nonspecific features (B). CD is plotted by ×, and ACS is plotted by ○. The Spearman’s rank correlation coefficients and P value are presented. CI confidence interval, CD Cushing’s disease, ACS adrenal Cushing’s syndrome

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)

	Patient-reported	Physician-assessed	P value of Fisher’s exact test	Concordance with Cohen’s kappa coefficient
A
Typical features
Moon face, n (%)	20 (39)	48 (92)	<0.01	Slight
Central obesity or buffalo hump, n (%)	13 (25)	44 (85)	<0.01	Slight
Purple striae, n (%)	3 (6)	15 (29)	<0.01	Fair
Thin skin and easy bruising, n (%)	15 (29)	43 (83)	<0.01	Slight
Proximal myopathy, n (%)	21 (40)	27 (52)	0.33	Slight
Nonspecific features
Hypertension, n (%)	39 (75)	43 (83)	0.47	Substantial
Menstrual abnormalities, n (%)	11 (21)	11 (21)	1.00	Almost perfect
Acne, n (%)	7 (14)	13 (25)	0.21	Moderate
Hirsutism, n (%)	3 (6)	10 (19)	0.07	Moderate
Peripheral edema, n (%)	24 (46)	28 (54)	0.56	Fair
Glucose metabolism impairment, n (%)	24 (46)	44 (85)	<0.01	Fair
Osteoporosis, n (%)	7 (14)	29 (56)	<0.01	Slight
Pigmentation, n (%)	0 (0)	5 (10)	0.06	–
Mental abnormalities, n (%)	17 (33)	17 (33)	1.00	Substantial
B
Typical features
Moon face, n (%)	6 (38)	14 (88)	0.01	Slight
Central obesity or buffalo hump, n (%)	6 (38)	15 (94)	<0.01	Slight
Purple striae, n (%)	2 (13)	4 (25)	0.56	Moderate
Thin skin and easy bruising, n (%)	4 (25)	13 (81)	0.06	Slight
Proximal myopathy, n (%)	8 (50)	8 (50)	1.00	Slight
Nonspecific features
Hypertension, n (%)	16 (100)	15 (94)	0.78	Slight
Menstrual abnormalities, n (%)	5 (31)	5 (31)	1.00	Almost perfect
Acne, n (%)	1 (6)	3 (19)	0.56	Moderate
Hirsutism, n (%)	2 (13)	4 (25)	0.56	Moderate
Peripheral edema, n (%)	8 (50)	10 (63)	0.56	Slight
Glucose metabolism impairment, n (%)	10 (63)	15 (94)	0.14	Slight
Osteoporosis, n (%)	4 (25)	9 (56)	0.15	Slight
Pigmentation, n (%)	0 (0)	5 (31)	0.14	–
Mental abnormalities, n (%)	5 (31)	6 (38)	0.78	Moderate
C
Typical features
Moon face, n (%)	14 (39)	34 (94)	<0.01	Slight
Central obesity or buffalo hump, n (%)	7 (19)	29 (81)	<0.01	Slight
Purple striae, n (%)	1 (3)	11 (31)	<0.01	Slight
Thin skin and easy bruising, n (%)	11 (31)	30 (83)	<0.01	Slight
Proximal myopathy, n (%)	13 (36)	19 (53)	0.24	Slight
Nonspecific features
Hypertension, n (%)	23 (64)	28 (78)	0.30	Substantial
Menstrual abnormalities, n (%)	6 (17)	6 (17)	1.00	Almost perfect
Acne, n (%)	6 (17)	10 (28)	0.40	Moderate
Hirsutism, n (%)	1 (3)	6 (17)	0.11	Fair
Peripheral edema, n (%)	16 (44)	18 (50)	0.81	Fair
Glucose metabolism impairment, n (%)	14 (39)	29 (81)	<0.01	Fair
Osteoporosis, n (%)	3 (8)	20 (56)	<0.01	Slight
Pigmentation, n (%)	0 (0)	0 (0)	–	–
Mental abnormalities, n (%)	12 (33)	11 (31)	1.00	Almost perfect

The frequencies of patient-reported and physician-assessed manifestations were compared using Fisher’s exact test. The concordance between patient-reported and physician-assessed manifestations was evaluated with Cohen’s kappa coefficient, and its coefficients were defined 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”

CD Cushing’s disease, ACS adrenal Cushing’s syndrome

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

	Univariate	Multivariate 1 (sex- and age-adjusted)	Multivariate 2 (BMI-adjusted)	Multivariate 3 (disease duration-adjusted)
A
Moon face	1.000 (0.999–1.001)	1.000 (0.999–1.001)	1.000 (0.998–1.002)	1.000 (0.999–1.001)
Proximal myopathy	1.000 (0.999–1.001)	1.000 (0.999–1.001)	1.000 (0.998–1.001)	1.000 (0.998–1.001)
Thin skin and easy bruising	1.000 (0.998–1.001)	1.000 (0.999–1.001)	1.000 (0.999–1.001)	1.000 (0.998–1.001)
Central obesity or buffalo hump	1.001 (1.000–1.003)	1.001 (1.000–1.003)	1.001 (1.000–1.003)	1.001 (1.000–1.003)
Purple striae	1.000 (0.999–1.002)	1.000 (0.998–1.002)	1.001 (0.999–1.003)	1.000 (0.999–1.002)
B
Moon face	0.998 (0.919–1.084)	0.999 (0.919–1.086)	1.000 (0.920–1.088)	0.997 (0.918–1.082)
Proximal myopathy	1.007 (0.925–1.097)	1.007 (0.924–1.097)	1.007 (0.925–1.097)	1.006 (0.924–1.096)
Thin skin and easy bruising	1.022 (0.939–1.112)	1.018 (0.934–1.109)	1.023 (0.940–1.113)	1.019 (0.937–1.109)
Central obesity or buffalo hump	0.979 (0.890–1.078)	0.978 (0.865–1.105)	0.981 (0.875–1.099)	0.978 (0.887–1.078)
Purple striae	0.998 (0.919–1.084)	0.999 (0.919–1.086)	1.000 (0.920–1.088)	0.997 (0.918–1.082)

The results are presented as odds ratios (95% confidence intervals)

UFC urinary free cortisol, BMI Body Mass Index, LDDST low-dose dexamethasone suppression test

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 [38‐41], 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.

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.

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.

Ethics approval

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

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

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Response to Osilodrostat Therapy in Adrenal Cushing’s Syndrome

Posted on April 15, 2024 by MaryO

Authors Stasiak M , Witek P, Adamska-Fita E, Lewiński A

Received 27 December 2023

Accepted for publication 20 March 2024

Published 8 April 2024 Volume 2024:16 Pages 35—42

DOI https://doi.org/10.2147/DHPS.S453105

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Hemalkumar B Mehta

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Magdalena Stasiak,¹ Przemysław Witek,² Emilia Adamska-Fita,¹ Andrzej Lewiński^1,³

¹Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital—Research Institute, Lodz, Poland; ²Department of Internal Medicine, Endocrinology and Diabetes, Medical University of Warsaw; Mazovian Brodnowski Hospital, Warszawa, Poland; ³Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Lodz, Poland

Correspondence: Magdalena Stasiak, Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital—Research Institute, 281/289 Rzgowska Street, Lodz, 93-338, Poland, Tel +48502049292, Fax +48422711140, Email mstasiak33@gmail.com

Abstract: Cushing’s disease (CD) is the most common cause of endogenous hypercortisolism. Osilodrostat was demonstrated to be efficient in treating CD, and the mean average dose required for CD control was < 11 mg/day. Potential differences in osilodrostat treatment between cortisol-producing adenoma (CPA) and CD have not been reported. The aim of this study was to present two patients with CPA in whom significant differences in the response to therapy compared to CD were found. We demonstrated a case of inverse response of cortisol levels with adrenal tumor progression during the initial dose escalation (Case 1). Simultaneously, severe exaggeration of hypercortisolism symptoms and life-threatening hypokalemia occurred. A further rapid dose increase resulted in the first noticeable cortisol response at a dose of 20 mg/day, and a full response at a dose of 45 mg/day. We also present a case that was initially resistant to therapy (Case 2). The doses required to achieve the first response and the full response were the same as those for Case 1. Our study demonstrated that osilodrostat therapy in patients with CPA may require a different approach than that in CD, with higher doses, faster dose escalation, and a possible initial inverse response or lack of response.

Keywords: osilodrostat, adrenal adenoma, hypercortisolism, ACTH-independent, adverse events, hypokalemia

Introduction

Chronic persistent hypercortisolism is a life-threatening condition that requires effective treatment. Untreated exposure to excessive cortisol secretion leads to severely increased morbidity and mortality due to cardiovascular diseases, thromboembolic events, sepsis, visceral obesity, impairment of glucose metabolism, and dyslipidaea, as well as musculoskeletal disorders, such as myopathy, osteoporosis, and skeletal fractures. Moreover, neuropsychiatric disorders, such as impairment of cognitive function, depression, or mania, as well as impairment of reproductive function can frequently occur.^1,2 Cushing’s disease (CD) – a disorder caused by a pituitary adenoma secreting adrenocorticotropic hormone (ACTH) – is the most common cause of hypercortisolism. Cushing’s syndrome (CS) includes all other causes of cortisol excess, including ectopic ACTH production as well as direct cortisol overproduction by adrenal adenoma (cortisol-producing adenoma [CPA]) or adrenocortical carcinoma (ACC). Approximately 10% of hypercortisolism cases result from CPA. The first line therapy is a surgical resection of the tumor, which is the source of hormone excess. However, in many patients surgery is not fully efficient and other therapies are required to reduce cortisol levels. Additionally, due to severe cardiovascular complications and unstable DM, the surgical approach sometimes entails unacceptable risk and it is frequently postponed until cortisol levels are lowered. Pharmacotherapy with steroidogenesis inhibitors reduces cortisol levels and improves the symptoms of hypercortisolism.^1,2 As CD is the most common cause of cortisol excess, most studies have focused on the efficacy and safety of novel steroidogenesis inhibitors, including patients with CD only.^3–6 This is exactly the case with osilodrostat – a new potent inhibitor of 11β-hydroxylase.^3–6 More data are available for metyrapone efficacy and safety in CSA,⁷ as the drug has been available much longer than osilodrostat. A study by Detomas et al, which reported results of comparison of efficacy of metyrapone and osilodrostat, included 4 patients with adrenal CS, among whom one CPA patient was treated with osilodrostat.⁸ Osilodrostat is approved in the United States to treat CD in patients in whom pituitary surgery was not curative or is contraindicated.⁹ In Poland, osilodrostat therapy is available for patients with all kinds of endogenous hypercortisolism not curative with other approaches, within a national program of emergency access to drug technologies.¹⁰ Reports on osilodrostat application in CPA are highly valuable as data on potential differences in the treatment regimens between CD and CPA are scarce.

Here, we present two patients with CPA in whom the response and doses of osilodrostat were different from those reported in patients with CD. The main purpose of this study was to demonstrate that the efficacy of osilodrostat in CPA is high, although initial resistance to treatment or even deterioration of hypercortisolism can occur during the application of lower doses of the drug.

Materials and Methods

Study Design and Patients

We retrospectively analyzed medical files of two consecutive patients with CPA treated with osilodrostat. The analysis included medical history, laboratory and imaging results as well as a detailed reports of adverse events.

Laboratory and Imaging Procedures

Serum cortisol and ACTH levels were measured by electrochemiluminescence immunoassay (ECLIA) using a Cobas e601 analyzer (Roche Diagnostics, Indianapolis, IN, USA). UFC excretion was measured by chemiluminescent microparticle immunoassay (CMIA) using an Abbott Architect ci4100 analyzer (Abbott, Abbott Park, IL, USA). Cross-reactivity with 11-deoxycortisol for this method is very low (2.1% according to the manufacturer’s data). Potassium levels were measured by ion-selective electrode potentiometry using a Beckman Coulter DxC 700 AU Chemistry Analyzer (Beckman Coulter, Brea, CA, USA). Computed tomography (CT) imaging was performed using a Philips Ingenuity Core 128 system (Philips, the Netherlands).

Ethics Procedures

Informed consent was obtained from all subjects involved in the study. Written informed consent was obtained from the patients for publication of this paper. The approval of Institutional Ethics Committee was obtained to publish the case details (approval code KB 33/2023).

Presentation of the Cases

Case 1

A 51-year-old female was referred to our department in November 2021 because of CPA, disqualified from surgery because of severe hypertension with a poor response to antihypertensive therapy and uncontrolled DM despite high doses of insulin. Additionally, the patient presented with hyperlipidemia and severe obesity (BMI=50.7 kg/m²), gastritis, depression, and osteoarthritis. On admission, she complained of a tendency to gain weight, fragile skin that bruised easily, difficulty with wound healing, susceptibility to infections, and insomnia. Physical examination revealed a moon face with plethora, a buffalo hump, central obesity with proximal muscle atrophy, and purple abdominal striae.

The CPA diagnosis was initially made two years earlier, but the patient did not qualify for surgery due to a hypertensive crisis. Soon after this episode, the SARS-CoV-2 pandemic began, and the patient was afraid of visiting any medical center because her son had died of COVID-19. Therefore, she was referred to our center for life-threatening hypercortisolism two years later.

At the time of admission, computed tomography (CT) imaging revealed a right adrenal tumor of 34x24x37mm, with a basal density of 21 HU and a contrast washout rate typical for adenomas (83%). The size and CT characteristics were identical as they were two years earlier. High serum cortisol levels, undetectable ACTH concentrations, and a lack of physiological diurnal rhythm of cortisol secretion were observed (Table 1). Urinary free cortisol (UFC) excretion was 310 µg/24 h, with an upper normal limit (UNL) of 176 µg/24 h. No cortisol suppression was achieved in high-dose dexamethasone suppression test (DST) (Table 1). Other adrenal-related hormonal parameters were within normal ranges, with values as follows: DHEA-S 42.68 µg/dl, aldosterone 3.24 ng/mL, and renin 59.14 µIU/mL.

Table 1 Laboratory Results Before Osilodrostat Therapy – Case 1

Due to multiple severe systemic complications, including uncontrolled hypertension, decompensated DM, and cardiac insufficiency, treatment with osilodrostat was introduced for life-saving pre-surgical management. Osilodrostat was started at a dose of 1 mg twice daily and gradually increased to 6 mg per day with actually an inverse response of serum cortisol level. The late-night cortisol level increased from 16 µg/dl to 25 µg/dl. As the full effect of the osilodrostat dose can occur even after a few weeks, the patient was discharged from hospital and instructed to contact her attending doctor immediately if any health deterioration was noticed. In the case of improvement in the patient’s condition, the next hospitalization was planned 3 weeks later. After three weeks of no contact with the patient, she was readmitted to our department with life-threatening escalation of hypercortisolism, severe hypokalemia, and further deterioration of hypertension, DM, cardiac insufficiency, dyspnea, and significant edemas, including facial edema. Treatments of hypertension, cardiac insufficiency, and DM were intensified, as presented in Table 2. Despite active potassium supplementation, life-threatening hypokalemia of 2.1 mmol/l occurred. Previously observed depression was exaggerated with severe anxiety and fear of death. The dose of osilodrostat was increased to 8 mg/day, and after three days of treatment a further elevation of serum cortisol was found, with an increase in UFC up to 9 × UNL (1546.2 µg/24 h). Due to an entirely unexpected inverse cortisol response, CT imaging was performed and revealed progression of the adenoma size to 39 × 36 × 40 mm, with a slight increase in density up to 27 HU as compared to the previous CT scan performed a month earlier (Figure 1).

Table 2 Changes in the Most Important Parameters During Osilodrostat Therapy – Case 1

Figure 1 Progression of the adrenal adenoma size during the initial doses of osilodrostat: (a) CT scan directly before osilodrostat therapy – solid nodule 34x24x37 mm, basal density 21 HU; (b) CT scan during treatment with 8 mg of osilodrostat daily – solid nodule 39x36x40 mm, basal density of 27 HU.

Considering the extremely high risk associated with such a rapid cortisol increase and related complications, decision of fast osilodrostat dose escalation was made. The dose was increased by 5 mg every other day, up to 45 mg per day, and, finally, a gradual decrease in the cortisol level (Table 2) was achieved, with UFC normalization to 168 µg/24 h. During dose escalation, no deterioration in the adverse effects (AEs) of osilodrostat was observed. Conversely, hypokalemia gradually improved despite a simultaneous reduction in potassium supplementation (Table 2). Facial edema decreased and the level of anxiety improved significantly. The course of hypertension severity as well as a summary of the main parameters controlled during treatment and the medications used are presented in Table 2. As soon as the cortisol level normalized, the patient was referred for surgery and underwent right adrenalectomy without any complications. Histopathology results confirmed a benign adenoma of the right adrenal gland (encapsulated, well-circumscribed tumor consisting of lipid-rich cells with small and uniform nuclei, mostly with eosinophilic intracytoplasmic inclusions). After surgery, hydrocortisone replacement therapy was administered. A few days after surgery, blood pressure and glucose levels gradually decreased, and the patient required reduction of antihypertensive and antidiabetic medications. After 22 months of follow-up, the patient’s general condition is good with no signs of recurrence. Antidepressant treatment is no longer required in this patient. Body mass index was significantly reduced to 40 kg/m². The antihypertensive medication was completely discontinued, and the glucose level is controlled only with metformin. The patient still requires hydrocortisone substitution at a dose of 30 mg/day.

Case 2

A 39-year-old female was referred to our department in November 2022 with a diagnosis of CPA and unstable hypertension, for which surgery was contraindicated. The patient was unsuccessfully treated with triple antihypertensive therapy (telmisartan 40 mg/day, nebivolol 5 mg/day, and lercanidipine 20 mg/day). The patient reported weight gain, muscle weakness, acne, fragile skin that bruised easily, and secondary amenorrhea. Other comorbidities included gastritis, hypercholesterolemia, and osteoporosis. Physical examination revealed typical signs of Cushing’s syndrome, such as abnormal fat distribution, particularly in the abdomen and supraclavicular fossae, proximal muscle atrophy, moon face, and multiple hematomas. A lack of a serum cortisol diurnal rhythm with high late-night serum cortisol and undetectable ACTH levels was found (Table 3). The short DST revealed no cortisol suppression (Table 3), and the UFC result was 725 µg/24 h, which exceeded the UNL more than four times. The serum levels of renin, aldosterone, and 24-h urine fractionated metanephrines were within the normal ranges. Computed tomography imaging revealed a left adrenal gland tumor measuring 25 × 26 × 22 mm, with a basal density of 32 HU and a washout rate typical for adenoma (76%).

Table 3 Laboratory Results Before Osilodrostat Therapy – Case 2

Osilodrostat therapy was administered for preoperative management. The initial daily dose was 2 mg/day, increased gradually by 2 mg every day with no serum cortisol response (late night cortisol levels 15.8–18.5 µg/dl) and no AEs of the drug (Table 4). After the daily dose of osilodrostat reached 10 mg, it was escalated by 5 mg every other day, initially with no serum cortisol reduction. The dose was increased to 45 mg daily (with the lowest detected late-night serum cortisol of 9.6 µg/dl) (Table 4).

Table 4 Changes in the Most Important Parameters During Osilodrostat Therapy – Case 2

After a week of administration of 45 mg daily, UFC normalization was achieved. Despite rapid dose escalation, no AEs were observed during the entire therapy period. Potassium levels were normal without any supplementation (the lowest detected serum potassium level was 3.9 mmol/l; all other results were over 4.0 mmol/l) (Table 4). After UFC normalization, left adrenalectomy was performed without complications. Histopathological examination revealed benign adrenal adenoma. Antihypertensive therapy was reduced only to 2.5 mg of nebivolol daily. The patient’s general condition improved significantly. Currently, hydrocortisone replacement therapy is administered at a dose of 15 mg/day.

Discussion

Osilodrostat is a novel potent steroidogenesis inhibitor whose efficacy and safety have been thoroughly analyzed in clinical trials of patients with CD, the most common cause of endogenous hypercortisolism. No clinical trial of osilodrostat therapy in CPA has been performed, as this disease constitutes only 10% of all cases of endogenous hypercortisolism. Moreover, osilodrostat is not approved by the FDA for hypercortisolism conditions other than CD.⁹ Therefore, data on potential differences in the treatment regimen are lacking.

During the course of already reported trials in CD, osilodrostat doses were escalated slowly, every 2–3 weeks,^3,5,6 with an excellent response to quite low doses of the drug.^3–6 In the LINC 2 extension study the median average dose was 10.6 mg/day,⁵ while in the LINC 3 extension study and the LINC 4 study it was 7.4 mg/day and 6.9 mg/day, respectively.^4,6 In most cases, a significant decrease of hypercortisolism was reported with the low doses of osilodrostat (4 or 10 mg/day). Moreover, some patients received 1 mg/day or even 1 mg every other day, with a good response.⁶ Even in rare cases of CD in whom initial short-term etomidate therapy was given at the beginning of osilodrostat therapy, due to highly severe life-threatening symptoms of hypercortisolism, the final effective dose of osilodrostat was much lower than that in our patients with CPA (25 mg/day vs 45 mg/day) and no increase of cortisol level was observed.¹¹

It should be underlined that many cases of adrenal insufficiency during osilodrostat therapy in patients with CD have been reported,^3–6,12,13 and – therefore – low initial dose with slow gradual dose escalation is recommended in patients with CD.^1,6,13

In the cases presented here, CPA led to severe hypercortisolism, the complications of which constituted contraindications for surgery. Therefore, osilodrostat therapy was introduced as a presurgical treatment. In Case 1, the therapy was started at low doses according to the approved product characteristics.¹⁴ Due to the severity of hypertension, which was uncontrolled despite of active antihypertensive therapy, as well as to unstable DM, the doses were increased faster than recommended. Surprisingly, we immediately observed a gradual increase in hypercortisolism, in both serum cortisol levels and the UFC, with simultaneous burst of complications related to both hypercortisolism itself and 11β-hydroxylase inhibition. Life-threatening episodes of hypertensive crisis responded poorly to standard therapies. Severe exaggeration of cardiac insufficiency could probably be related to these episodes as well as to deep hypokalemia, which occurred despite potassium supplementation. Hypokalemia is a typical complication of treatment with 11β-hydroxylase inhibitors due to the accumulation of adrenal hormone precursors. However, Patient 1 required much higher doses of potassium supplementation, both parenteral and oral, than ever described during osilodrostat therapy.^3–6,13 The dose of 20 mg/day of osilodrostat was the first one which led to noticeable cortisol reduction and a decrease in systolic blood pressure (SBP) to below 170 mmHg. Surprisingly, instead of the expected deterioration of hypokalemia, parenteral potassium administration could be stopped with an osilodrostat dose of 20 mg/day and oral supplementation was gradually reduced simultaneously with osilodrostat dose escalation. The reason why such severe hypokalemia occurred with low doses of osilodrostat and did not deteriorate further seems complex. One possible reason is the administration of high doses of potassium-saving antihypertensive drugs such as spironolactone and the angiotensin II receptor antagonist telmisartan. Additionally, one can consider other possible mechanisms, such as downregulation of the receptors of deoxycorticosterone (DOC) or other adrenal hormone precursors. However, this hypothesis requires further research and confirmation. Such an improvement of the potassium level during osilodrostat dose escalation was previously demonstrated in a patient with CD.¹¹ Interestingly, in our Patient 2, no potassium supplementation was required during the whole time of osilodrostat therapy, although the doses were increased intensively up to the finally effective dose, which was the same (45 mg/day) as for Patient 1. In Patient 2, no actual response to doses lower than 20 mg/day was observed. UFC normalization was achieved after a week of administration of 45 mg/day, five weeks from the beginning of therapy. Although UFC normalization is not always required in pre-surgical treatment, clinical symptoms significantly improved in our patients only after the UFC upper normal level was achieved.

The present paper is one of only a few reports focused on osilodrostat therapy in CPA, and the only one presenting a different therapy course as compared to patients with CD. No case of CPA resistance to low doses of osilodrostat has been described. It should be underlined that in our report “low doses” of osilodrostat were higher than the average mean doses of osilodrostat used in clinical trials in patients with CD.^3–6 Therefore, they should not generally be considered low but only much lower than those which were effective in our patients. Malik and Ben-Shlomo presented a case of CPA treated with osilodrostat, with an immediate decrease in cortisol level at 4 mg/day and adrenal insufficiency symptoms after dose escalation to 8 mg/day.¹⁵ Similar to our two cases, their patient was a middle-aged female with normal results of all other adrenal parameters, such as renin, angiotensin, or metanephrine levels. However, a CT scan was not performed (or presented), while magnetic resonance imaging revealed an indeterminate adrenal gland mass without a typical contrast phase/out-of-phase dropout for adenoma.¹⁵ Therefore, different morphology of cortisol-secreting adrenal tumor can potentially be considered a reason of the different response to treatment. Tanaka et al performed a multicenter study on the efficacy and safety of osilodrostat in Japanese patients with non-CD Cushing’s syndrome.¹⁶ Five patients with CPA were included in the study, and none of them required osilodrostat doses higher than 10 mg/day to achieve UFC normalization. However, most of the patients presented by Tanaka et al were previously treated with metyrapone,¹⁶ whereas both of our patients were treatment-naive. Previous metyrapone therapy may be considered as a potential reason of better response to osilodrostat. This hypothesis was confirmed in the quoted study by Tanaka et al, who demonstrated that at week 12 the median percent changes in the mUFC values were higher in patients previously treated with metyrapone (–98.97%) than in treatment-naive cases (–86.65%).¹⁶ Detomas et al performed a comparison of efficacy and safety of osilodrostat and metyrapone, with one CPA patients included in a group treated with osilodrostat, however no data on a dose required for a disease control are available separately for this particular patient.⁸ To the best of our knowledge, no more CPA cases have been described and therefore no further comparison is available.

Higher doses of osilodrostat were administered to a group of seven patients with hypercortisolism due to adrenocortical carcinoma (ACC) presented by Tabarin et al.¹⁷ A full control of hypercortisolism was achieved in one patient for each dose of 4, 8, 10, and 20 mg/day, and in three patients treated with 40 mg/day.¹⁷ These patients, however received other therapies including mitotane and chemotherapy, which can significantly modify the response to osilodrostat.

Several authors have reported the phenomenon of a partial or total loss of response to osilodrostat.^5,16,17 In such cases, a response to treatment was initially achieved and then lost during treatment with the same dose. A further increase in osilodrostat dose usually resulted in the response resumption.^5,16,17 Such a situation could not be suspected in either of our cases.

The presented cases provide a novel insight into modalities of treatment with osilodrostat in patients with CPA and demonstrate for the first time that an inverse cortisol response is possible in CPA cases, especially those with a higher CT density of adrenal adenoma. Such a situation should not be considered a contraindication to dose escalation. Conversely, the dose should be increased more intensively so as to achieve the initial efficacy threshold, which was 20 mg/day in both of our patients. The fully efficient dose that allowed UFC normalization was more than twice as high (45 mg/day in both cases). A similar approach should be applied in patients who do not respond to lower doses, such as Patient 2. The safety of osilodrostat therapy is strictly individual and not dose dependent in patients with CPA. Adverse events, including hypokalemia, severe hypertension, and edema, can be of life-threatening severity or may not occur regardless of the dose. Moreover, AEs of high severity may decrease with osilodrostat dose escalation. Our study demonstrated that osilodrostat is efficient and can be used in patients with CPA as a pre-surgical therapy if surgery is contraindicated due to hypercortisolism complications.

Our study presented two cases of CPA treated with osilodrostat, and a small size of our group is the main limitation of this report. Future research is required to confirm our observations.

Conclusion

In some patients with CPA, the doses of osilodrostat required for disease control can be much higher than those previously reported. Acceleration of the dose increase can be fast, and the risk of overdosing, adrenal insufficiency, and later necessity of dose reduction seem to be much lower than it could be expected. Low initial doses (<20 mg/day in our study) can be entirely ineffective or can even cause exacerbation of hypercortisolism, whereas high doses (45 mg/day in the present study) are efficient in pre-surgery UFC normalization. AEs associated with osilodrostat can be rapid, with severe hypokalemia despite active potassium supplementation, or may not occur even if high doses of osilodrostat are applied. Therefore, close monitoring for potential AEs is necessary.

Acknowledgments

The abstract included some parts of this paper was presented at the European Congress of Endocrinology ECE2023 as a rapid communication. The abstract was published in the Endocrine Abstracts Vol. 90 [https://www.endocrine-abstracts.org/ea/0090/].

Funding

The publication of this report was financially supported by the statutory funds of the Polish Mother’s Memorial Hospital – Research Institute, Lodz, Poland.

Disclosure

Professor Przemysław Witek reports personal fees from Investigator in the clinical trials paid by Novartis and Recordati Rare Diseases, outside the submitted work; lectures fees from Recordati Rare Diseases, Strongbridge, IPSEN. The authors report no other conflicts of interest in this work.

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2. Pivonello R, Isidori AM, De Martino MC, et al. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4(7):611–629. doi:10.1016/S2213-8587(16)00086-3

3. Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre Phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;8(9):48–761. doi:10.1016/S2213-8587(20)30240-0

4. Fleseriu M, Newell-Price J, Pivonello R, et al. Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension. Eur J Endocrinol. 2022;187(4):531–541. doi:10.1530/EJE-22-0317

5. Fleseriu M, Biller BMK, Bertherat J, et al. Long-term efficacy and safety of osilodrostat in Cushing’s disease: final results from a Phase II study with an optional extension phase (LINC 2). Pituitary. 2022;25(6):959–970. doi:10.1007/s11102-022-01280-6

6. Gadelha M, Bex M, Feelders RA, et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab. 2022;107(7):e2882–e2895. doi:10.1210/clinem/dgac178

7. Daniel E, Aylwin S, Mustafa O, et al. Effectiveness of metyrapone in treating cushing’s syndrome: a retrospective multicenter study in 195 patients. J Clin Endocrinol Metab. 2015;100(11):4146–4154. doi:10.1210/jc.2015-2616

8. Detomas M, Altieri B, Deutschbein T, et al. Metyrapone versus osilodrostat in the short-term therapy of endogenous cushing’s syndrome: results from a single center cohort study. Front Endocrinol. 2022;13:903545. doi:10.3389/fendo.2022.903545

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16. Tanaka T, Satoh F, Ujihara M, et al. A multicenter, Phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing’s syndrome other than Cushing’s disease. Endocr J. 2020;67(8):841–852. doi:10.1507/endocrj.EJ19-0617

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Cushing’s Syndrome Subtype Affects Postoperative Time to Adrenal Recovery

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Cushing’s Syndrome Etiology Affects Adrenal Function Recovery

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Adrenal Cushing’s Syndrome in Pregnancy Complicated by Fetal Growth Restriction Following Retroperitoneoscopic Adrenalectomy

Abstract

Introduction

Case Presentation

Figure 1: Macroscopic findings characteristic of Cushing’s syndrome

Table 1: Laboratory data of CBC, serum biochemistry, and endocrinology

Table 2: Laboratory data of 75-g OGTT and urinalysis

Table 3: Laboratory data of ACTH/F diurnal rhythm

Figure 2: Radiological findings of the right adrenal tumor (white arrow)

Figure 3: Obstetric ultrasonography

Figure 4: Clinical course between hospitalization and cesarean delivery

Figure 5: Photograph showing the patient in the left lateral decubitus position after general anethesia

Figure 6: Histopathological findings of the right adrenal gland (A, B, C) and placenta (D)

Figure 7: Trends in estimated fetal body weight (EFBW) and standard deviation (SD)

Discussion

Conclusions

References

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Diagnostic dilemma in Cushing’s syndrome: discrepancy between patient-reported and physician-assessed manifestations

Purpose

Methods

Results

Conclusion

Introduction

Materials and methods

Patients, study design, and data collection

Definition of patient-reported and physician-assessed manifestations

Comorbidities of Cushing’s syndrome

Hormone assay

Statistical analysis

Results

Clinical characteristics of the patients

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

Discussion

Acknowledgements

Compliance with ethical standards

Conflict of interest

Ethics approval

Informed consent

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Response to Osilodrostat Therapy in Adrenal Cushing’s Syndrome

Introduction

Materials and Methods

Study Design and Patients

Laboratory and Imaging Procedures

Ethics Procedures

Presentation of the Cases

Case 1

Case 2

Discussion

Conclusion

Acknowledgments

Funding

Disclosure

References

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