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.

Macroscopic-findings-characteristic-of-Cushing’s-syndrome
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

Radiological-findings-of-the-right-adrenal-tumor-(white-arrow)
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.

Obstetric-ultrasonography
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).

Clinical-course-between-hospitalization-and-cesarean-delivery
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).

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

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

Histopathological-findings-of-the-right-adrenal-gland-(A,-B,-C)-and-placenta-(D)
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).

(C) Tumor cells with abundant eosinophilic to clear cytoplasm arranged in a trabecular to microacinar growth pattern.

(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.

Trends-in-estimated-fetal-body-weight-(EFBW)-and-standard-deviation-(SD)
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.

References

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  3. Caimari F, Valassi E, Garbayo P, Steffensen C, Santos A, Corcoy R, Webb SM: Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases. Endocrine. 2017, 55:555-63. 10.1007/s12020-016-1117-0
  4. Hamblin R, Coulden A, Fountas A, Karavitaki N: The diagnosis and management of Cushing’s syndrome in pregnancy. J Neuroendocrinol. 2022, 34:e13118. 10.1111/jne.13118
  5. Sammour RN, Saiegh L, Matter I, et al.: Adrenalectomy for adrenocortical adenoma causing Cushing’s syndrome in pregnancy: a case report and review of literature. Eur J Obstet Gynecol Reprod Biol. 2012, 165:1-7. 10.1016/j.ejogrb.2012.05.030
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  7. Younes N, St-Jean M, Bourdeau I, Lacroix A: Endogenous Cushing’s syndrome during pregnancy. Rev Endocr Metab Disord. 2023, 24:23-38. 10.1007/s11154-022-09731-y
  8. Sasaki A, Shinkawa O, Margioris AN, et al.: Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor, and delivery. J Clin Endocrinol Metab. 1987, 64:224-9. 10.1210/jcem-64-2-224
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  16. Xiao D, Huang X, Bae S, Ducsay CA, Zhang L: Cortisol-mediated potentiation of uterine artery contractility: effect of pregnancy. Am J Physiol Heart Circ Physiol. 2002, 283:H238-46. 10.1152/ajpheart.00842.2001
  17. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS: Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol. 1994, 105:11-17. 10.1016/0303-7207(94)90176-7
  18. Wang Y, An Y, Hou X, et al.: Cushing’s syndrome in pregnancy secondary to adrenocortical adenoma: a case series and review. Endocrinol Diabetes Metab. 2024, 7:e00474. 10.1002/edm2.474
  19. Shaw JA, Pearson DW, Krukowski ZH, Fisher PM, Bevan JS: Cushing’s syndrome during pregnancy: curative adrenalectomy at 31 weeks gestation. Eur J Obstet Gynecol Reprod Biol. 2002, 105:189-91. 10.1016/s0301-2115(02)00148-3
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Prospective Assessment of Mood and Quality of Life in Cushing Syndrome Before and After Biochemical Control

Posted on November 27, 2025 by MaryO

Abstract

Context

Cushing’s syndrome (CS) impairs quality of life (QoL) and mood. Prospective real-life data on posttreatment recovery and predictors of improvement are limited.

Objectives

Evaluate changes in QoL, depression, and anxiety in patients with CS, before and after biochemical control, and identify predictors of clinically meaningful improvement.

Design and Setting

Prospective observational study at a tertiary center.

Patients

Sixty-seven patients with endogenous CS (60 pituitary, 7 adrenal) were assessed with active disease and again after achieving biochemical control through surgery and/or medication.

Outcomes

Patient-reported outcomes included CushingQoL, Beck Depression Inventory-II (BDI-II), and State-Trait Anxiety Inventory (STAI).

Results

Mean and longest follow-up was 2.3 and 11.5 years, respectively. Treatment led to improvements in mean scores across all domains (QoL: +18.2 ± 20.9, BDI-II: −6.8 ± 8.6, STAI-State: −9.6 ± 12.5, STAI-Trait: −8.6 ± 12.6; all P < .001). However, a minimal important difference was achieved in 64.6% for QoL, 67.9% for BDI-II, and 53.2% and 52.8% for STAI subscales. After multivariable analysis, QoL improvements were predicted by lower baseline body mass index, pretreatment symptoms ❤ years, postoperative hydrocortisone replacement >6 months, and normal follow-up late-night salivary cortisol (LNSC). Depression improvements were predicted by symptoms ❤ years, normal follow-up LNSC, and surgical treatment. Anxiety improvements were predicted by younger age and >6 months postoperative hydrocortisone. Depression improved more gradually than QoL and anxiety.

Conclusion

Although effective treatment improves mood and QoL in CS, clinically meaningful recovery is variable and incomplete for some patients. Our findings highlight the need to limit diagnostic delay and provide comprehensive posttreatment care that includes normalization of cortisol circadian rhythm.

Endogenous Cushing’s syndrome (CS) is a rare disorder characterized by chronic cortisol excess, most commonly due to an ACTH-secreting pituitary tumor [Cushing disease (CD)], followed by a cortisol-secreting adrenal adenoma and ectopic ACTH production due to a nonpituitary tumor (1). CS is associated with multiple comorbidities including diabetes, obesity, hypertension, immune suppression, osteoporosis, and cardiovascular disease, among others (2). Apart from these, patients face a spectrum of neuropsychiatric disturbances including depression, anxiety, mania, sleep disorders, and even psychosis. These comorbidities significantly disturb quality of life (QoL) and may persist long after treatment (3-7).

As with many rare diseases, CS remains incompletely understood, and patients experience impaired disease perception, information gaps, and isolation. In this context, patient-reported outcomes (PROs) have become useful instruments to clarify these gaps and guide patient-centered care. Disease-specific tools (CushingQoL, Tuebingen CD-25) and generic mood scales (Beck Depression Inventory, State-Trait Anxiety Inventory [STAI; including State (STAI-S) and Trait (STAI-T), Hospital Anxiety and Depression Scale] have established impairments in QoL and mood both during active disease and in remission (4, 8-11).

Although improvements are noted with treatment, recovery does not seem to be complete. Studies have reported persistently reduced QoL compared to the general population and the presence of depressive symptoms even 12 months postoperatively (4, 9). Findings regarding anxiety are less consistent: while some studies did not support the increased prevalence of anxiety in patients with active CS compared to the general population (12), others reported higher anxiety traits among patients with CS (during active disease and in remission) (13, 14) with steady improvement at 6- and 12-month follow-up (15). Clinical trials with adrenal steroidogenesis inhibitors or pasireotide demonstrated that effective biochemical control can improve QoL and depression (16-18). However, it is unclear whether these improvements are clinically significant and if patients achieve normal QoL and depression scores.

The role of PROs in assessing recovery during the treatment journey of patients with CS has not been clearly established, and QoL and mood trajectories remain unclear, largely due to small samples, limited follow-up, and cross-sectional designs. Among available prospective studies using PROs in CS, only 3 (2 evaluating pasireotide and 1 osilodrostat) reported the proportion of patients who met the minimal important difference (MID), which is the score change reflecting a clinically meaningful improvement (17-19), while others have only reported statistically significant changes in mean score, an important but possibly less clinically relevant outcome (20-22). Real-world clinical management adds further complexity: postoperative glucocorticoid replacement, potential glucocorticoid-withdrawal symptoms, and 20% to 30% recurrence rates after initial surgical “cure” all suggest that, for many patients, recovery may follow a nonlinear course. To date, no clinical practice prospective study has systematically assessed QoL and mood across multiple timepoints, compared surgical and medical strategies within a single cohort, and limited inclusion to patients who achieved biochemical remission or control for at least 6 months. Therefore, the aims of this study were to evaluate changes in QoL, depression, and anxiety in a clinical practice cohort of patients with CS before and over time after biochemical control, report achievement rates of MID, and identify predictors of clinically meaningful improvement.

Methods

Study Design

This study includes prospective data from patients enrolled in an ongoing observational cohort study, which since 2017 enrolls patients with endogenous CS at Memorial Sloan Kettering Cancer Center (MSKCC) [prior to 2017, enrollment took place at Mount Sinai (2012-2017)]. In this protocol, CS patients being treated at the MSKCC Pituitary and Skull Base Tumor Center are enrolled at any point in their treatment journey and prospectively followed over time after surgical, medical, and/or radiation treatment. At each study visit, a detailed medical history and biochemical and clinical data are collected according to standard of care. Patients also complete validated psychological and QoL assessments.

The current analysis includes a cohort of 67 patients with CS: 60 with pituitary and 7 with adrenal CS. Each patient completed a baseline (active disease) visit and at least 1 follow-up visit after achieving surgical remission or endocrine control due to medical therapy.

From the total of 67 patients, we analyzed 73 distinct baseline-to-follow-up case pairs. Six patients experienced recurrence after surgery or were inadequately controlled while on medical therapy after their initial follow-up visit and underwent a subsequent change in treatment strategy. These instances were treated as separate case pairs when needed, enabling comparison of different treatment approaches. When analyzing for a single follow-up, visits were grouped by time: group 1 (G1): 6 months, group 2 (G2): 12-18 months, and group 3 (G3): 24 or more months posttreatment. Each patient contributed to 1 or multiple groups based on the number of their study visits. For patients with multiple visits receiving different treatments throughout the current study, each follow-up visit was categorized based on time since the most recent intervention to ensure that we assessed outcomes according to the duration of biochemical control. For patients who underwent surgery, the follow-up interval was calculated from the date of surgery; for those on medical therapy, it was calculated from the start of medication. In the subanalysis comparing treatment- or demographic-related score changes, the most recent available follow-up was used in each case. At each visit patients completed at least 1 of the following: Cushing QoL, Beck Depression Inventory-II (BDI-II), or STAI-S and STAI-T.

For multiple follow-up visits during remission or treatment, 28 patients were evaluated. For this subgroup, we examined their whole trajectory over time. We then stratified this subgroup by total follow-up duration (<2 years vs ≥2 years) and assessed for significant differences between these 2 categories where applicable.

For the baseline visit, ACTH-dependent pituitary and ACTH-independent adrenal Cushing’s was confirmed according to Endocrine Society guidelines (23). Surgical remission was defined as postoperative serum cortisol <5 μg/dL (<138 nmol/L) and requirement of glucocorticoid replacement, according to the Endocrine Society’s guidelines and the Pituitary Society’s recent consensus statement (24, 25). For patients managed medically, endocrine control was defined as normalization of 24-hour urinary free cortisol (UFC) and based on clinical review and assessment by E.B.G.

The study was approved by the institutional review board at MSKCC. All subjects gave written informed consent before participation.

Outcome Measurements

Cushing QoL

The Cushing QoL is a validated disease-specific questionnaire consisting of 12 questions on a 5-point scale ranging from “always” to “never” (for 10 questions) or “very much” to “not at all” (for 2 questions). Total score ranges from 12 to 60. This is converted to a 0 to 100 scale, with 0 indicating the worst and 100 the best QoL. It evaluates physical and psychological issues and can also be scored through these 2 distinct subscales. MID is defined as an increase of ≥10.1 (26).

BDI-II

The BDI-II is a validated 21-item patient-reported questionnaire. Patients self-rate each item on a scale from 0 to 3 based on how they were feeling during the past 2 weeks. Total score ranges from 0 (best) to 63 (worst); scores from 0 to 13 indicate no or minimal depression; 14 to 19, mild depression; 20 to 28, moderate depression; and 29 to 63, severe depression. MID is defined as a 20% reduction from baseline score (27, 28).

STAI

The STAI is an instrument with 2 subscales: State anxiety (STAI-S), which reflects the present moment, and Trait anxiety (STAI-T), which assesses a stable tendency toward anxiety. Both subscales consist of 20 items scored from 0 to 3. Total scores range from 0 to 60, with higher scores indicating greater anxiety. Prior studies suggest a change of 0.5× SDs—or approximately 5 to 10 points—as a reasonable threshold for MID. In our study, we defined the MID at 7 points, based on observed SD of change at 12.5 for STAI-S and 12.6 for STAI-T (29).

In this study, all score changes from baseline to follow-up were reported as positive values to uniformly represent improvement across measures. For BDI-II and STAI where higher scores indicate worse outcomes, the direction of change was inverted for consistency.

Hormone Assays

Hormone testing was performed at either the MSKCC clinical laboratory or external laboratories (Quest Diagnostics, Labcorp, Mayo Clinic Laboratories). Plasma ACTH was measured using Tosoh immunoassay [RRID:AB_2783633; normal range (NR): 7.4-64.3 pg/mL (1.6-14.2 pmol/L); MSKCC or 6 to 50 pg/mL (1.3-11.0 pmol/L); QuestDiagnostics] or electrochemiluminescence immunoassay [RRID:AB_3678556; NR: 7.2-63.3 pg/mL (1.6-13.9 pmol/L); LabCorp, Mayo Clinic Laboratories]. Serum cortisol was measured via either immunoassay [RRID:AB_2802133; NR: 4-22 µg/dL (110-607 nmol/L); QuestDiagnostics or 7-25 µg/dL (193-690 nmol/L); Mayo Clinic Laboratories], electrochemiluminescence immunoassay [RRID:AB_2802131; NR: 6.2-19.4 µg/dL; (171-535 nmol/L); LabCorp], or liquid chromatography–tandem mass spectrometry [LC-MS/MS; NR: 5-25 µg/dL (138-690 nmol/L)]. UFC was measured using LC-MS/MS [NR: 3.5-45 µg/24 hours (9.7-124 nmol/24 hours); MSKCC, Mayo Clinic Laboratories or 3.0 to 50 µg/24 hours (8.3-138 nmol/24 hours); Quest Diagnostics, LabCorp]. Late-night salivary cortisol (LNSC) was assessed via LC-MS/MS [NR: ≤ 0.09 µg/dL (2.5 nmol/L); QuestDiagnostics, LabCorp or <100 ng/dL (27.6 nmol/L); MSKCC, Mayo Clinic Laboratories]. LNSC values were analyzed categorically (normal vs abnormal), and patients were asked to provide 2 LNSC samples on separate evenings. Abnormal LNSC was defined as at least 1 value above the upper limit of normal for the assigned laboratory.

Comorbidities

Diabetes mellitus (DM) was defined by any of the following: hemoglobin A1c (HbA1c) > 6.4%, fasting blood glucose (FBG) ≥ 126 mg/dL (7.0 mmol/L), or use of at least 1 antidiabetic medication. Pre-DM was defined as HbA1c between 5.7% and 6.4% or FBG between 100 and 125 mg/dL (5.6-6.9 mmol/L). Women taking metformin for polycystic ovary syndrome were classified as nondiabetic only if their HbA1c and FBG values both before metformin initiation and at the time of CS diagnosis remained within the normal range. Hypertension was defined as systolic blood pressure ≥ 130 mmHg, diastolic blood pressure ≥ 80 mmHg, or use of any antihypertensive medication.

Statistical Analysis

Analyses were conducted using IBM SPSS for Windows (version 29.0, IBM Corp.). Data normality was assessed by the Shapiro–Wilk test. Descriptive statistics were used for demographic and clinical characteristics. Normally distributed data were compared by Student’s t-test and nonnormally distributed variables with the Mann–Whitney U-test. Paired T-tests were conducted to study mean changes from baseline to a single follow-up visit. For categorical characteristics and the MID, we calculated the achievement rates and used Pearson’s chi-square for comparisons where applicable. For patients with more than 2 follow-up visits ANOVA (repeated measures) was applied for the trajectory of each measurement over time. To identify predictors of improvement, univariable linear regression models for score change and logistic regression for MID achievement were performed using baseline visit and longest follow-up visit for each patient. Variables with P ≤ .10 or of clinical relevance were then entered into multivariable regression models—again, linear regression for score change and logistic regression for MID achievement—where each predictor was separately evaluated, adjusting for age, sex, and baseline score. Correlation analyses were performed using Pearson or Spearman correlation coefficients for data with normal or abnormal distribution, respectively. Correlation coefficients (r) were interpreted as follows: values between 0.0 and ±0.3: weak, between ±0.3 and ±0.7: moderate, and between ±0.7 and ±1.0: strong relationships. All statistical tests were 2-sided, and results were considered significant with P ≤ .05.

Results

Study Participants

From a cohort of 226 endogenous CS and silent ACTH tumor patients enrolled in our ongoing MSKCC prospective cohort study, we identified patients who had a baseline visit with active hypercortisolism, who had at least 1 follow-up visit while in surgical remission or medical control, and who had completed at least 1 of the evaluated questionnaires correctly. After excluding patients with silent ACTH tumors, those with missing data, and follow-up visits that did not meet remission criteria, we included 67 patients (56 females, 11 males) with a mean baseline age of 42.3 ± 13.1 years. Among these patients, 60 had CD and 7 had adrenal CS.

Further patient demographic information is shown in Tables 1 and 2.

 
Table 1.

Demographics and baseline characteristics

Demographic variable n = 67 patients
Age, years
 Mean (SD) 42.3 (13.1)
 Range 20-75
Sex, n (%)
 Female 56 (83.6)
CS subtype, n (%)
 CD 60 (89.6)
 Adrenal CS 7(10.4)
Race, n (%)
 White 50 (74.6)
 Black/African American 8 (11.9)
 Asian 2 (3.0)
 Other/unknown 7 (10.4)
24-hour UFC
 Mean (SD) 391.5 (1471) µg/24 hours,
1080 (4060) nmol/24 hours
 Median (IQR) 135.0 (82.7-220.0) µg/24 hours, 372 (228-607) nmol/24 hours
 Range (min-max) 29-12 346 µg/24 hours, 80-34 053 nmol/24 hours
LNSC, n (%)
 Normal 3 (4.5)
 Abnormal 59 (88.1)
 NA 5 (7.5)
Plasma ACTH
 Mean (SD) 70.7 (64.1) pg/mL, 15.6 (14.1) pmol/L
 Median (IQR) 56.0 (42.0-83.8) pg/mL, 12.3 (9.2-18.4) pmol/L
 Range (min-max) 11-416 pg/mL (2.4-91.5 pmol/L)
Prior recurrence at baseline, n (%) 16 (23.9)
Prior transsphenoidal surgery, n (%) 16 (23.9)
 1 9 (13.4)
 2 7(10.4)

Abbreviations: CD, Cushing disease; CS, Cushing’s syndrome; IQR, interquartile range; LNSC, late-night salivary cortisol; NA, not available; UFC, urinary free cortisol.

 
Table 2.

Baseline and follow-up data

Baseline Longest follow-up P-value
BMI (kg/m2)
 Mean (SD) 33.2 (7.6) 30.6 (8.5) <.001
 Median (IQR) 31.6 (26.8-37.3) 29.3 (25.3-34.8)
LNSC, n (%) <.001
 Normal 3 (4.5) 30 (44.7)
 Abnormal 59 (88.1) 16 (23.8)
 NA 5 (7.5) 21 (31.3)
DM, n (%) <.001
 DM 28 (41.8) 13 (19.4)
 Pre-DM 15 (22.4) 9 (13.4)
Hypertension, n (%) 55 (82.1) 35 (53.7) <.001
HbA1C (%) <.001
 Total mean (SD) 6.5 (1.8) 5.7 (0.9)
 DM/pre-DM mean (SD) 6.9 (1.8) 6.1 (1.0)
Antidiabetic medications, n (%) 20 (29.9) (22.4)
 1 12 (17.9) (13.4)
 2 1 (1.5) (3.0)
 3 3 (4.5) (1.5)
 Insulin 4 (6.0) 3 (4.5)
Antihypertensive medications, n (%) 34 (50.7) (37.3)
 1 15 (22.4) (19.4)
 2 10 (14.9) (11.9)
 ≥3 9 (13.4) 4 (6.0)
Other medications, n (%)
 Antidepressants 10 (14.9) 13 (19.4)
 Anxiolytics 12 (17.9) 12(17.9)
 Pain medications 16 (23.9) 23 (34.3)
 Sleep medications 16 (23.9) 21 (31.3)
Treatment at most recent follow-up,a n (%)
 Transsphenoidal surgery 44 (65.7)
 Medical therapy 18 (26.9)
 Bilateral adrenalectomy 3 (4.5)
 Radiation therapy 1 (1.5)
 Adrenalectomy (adrenal CS) 7 (10.4)

Abbreviations: BMI, body mass index; CS, Cushing’s syndrome; DM, diabetes mellitus; HbA1c, hemoglobin A1c; IQR, interquartile range; LNSC, late-night salivary cortisol.

a“n” refers to number of separate baseline-to-follow-up cases.

In total, there were 46 visits in G1, 31 in G2, and 24 in G3. At the most recent follow-up of each case, there were 24 visits in G1, 25 in G2, and 24 in G3.

The mean (range) duration from baseline to most recent follow-up was 28.3 (5-138) months in the overall cohort. The mean (range) follow-up duration since the most recent treatment was 6.3 (4-9) months for G1, 12.7 (10-18) months for G2, and 43.7 (23-120) months for G3. At their final follow-up visit, 44 patients (65.7%) achieved remission after transsphenoidal surgery (TSS), 18 (26.9%) were under medical control, 3 (4.5%) underwent bilateral adrenalectomy (BLA), 1 (1.5%) received radiation therapy (RT), and the 7 (10.4%) patients with adrenal CS underwent unilateral adrenalectomy (Table 2).

The following additional treatments were administered between this study’s baseline visit and longest follow-up: among the 44 patients treated with TSS at their latest follow-up, 1 underwent an additional TSS and 1 received medical therapy prior to TSS. Of the 18 medically managed patients at last follow-up, 8 (44.4%) had previously undergone TSS (3 of whom had 2 TSSs), and 2 of these 8 additionally received at least 1 different medication before switching to the 1 recorded at their last follow-up. Two (11.1%) other patients received 2 sequential medications before the final 1 at follow-up, and 1 (5.6%) patient was on a block-and-replace regimen with hydrocortisone (HC) after 2 TSSs and BLA. The complete treatment journey of patients on medical therapy, before and after entering the study, is shown in Fig. 1. Among the patients who underwent BLA at last follow-up, 1 had 2 prior TSSs, 1 had a sin1 gle prior TSS and received medical therapy and had 2 TSSs and received medical therapy. The patient treated with RT had 2 prior TSSs and received medical therapy.

 

Treatment journey of the 18 patients on medical therapy at their longest follow-up. Each row represents the longitudinal treatment course of each patient before and/or after entering the study. Multiple boxes indicating medical therapy within the same patient represent different medications administered over time. Segments outlined in bold represent the follow-up period analyzed in the current cohort, from this' study baseline to the longest available follow-up.

Figure 1.

Treatment journey of the 18 patients on medical therapy at their longest follow-up. Each row represents the longitudinal treatment course of each patient before and/or after entering the study. Multiple boxes indicating medical therapy within the same patient represent different medications administered over time. Segments outlined in bold represent the follow-up period analyzed in the current cohort, from this’ study baseline to the longest available follow-up.

Abbreviations: CT, clinical trial; Keto, ketoconazole; Levo, levoketoconazole; Mety, metyrapone; Mife, mifepristone; Osilo, osilodrostat; Pasi, pasireotide.

Sixteen patients presented with recurrent disease; an additional 9 patients (13.4%) developed recurrent or persistent disease after surgery. HC replacement was administered at 21 of the longest available follow-up visits [6 due to ongoing hypopituitarism or adrenal insufficiency (AI) and 15 for temporary postoperative AI], with another 9 cases receiving replacement at intermediate follow-up visits.

All 18 patients on medical therapy at their longest follow-up received adrenal steroidogenesis inhibitors: osilodrostat (8 patients, 44.4%), metyrapone (6 patients, 33.3%), and ketoconazole (4 patients, 22.2%).

Comorbid Conditions

As shown in Table 2, mean body mass index (BMI) at baseline was 33.2 ± 7.6 kg/m2. Twenty-eight (41.8%) patients presented with DM, 15 (22.4%) with prediabetes, and 24 (35.8%) without DM. Fifty-five of 67 patients (82.1%) had hypertension at baseline. At the longest follow-up, mean BMI decreased to 30.6 ± 8.5 kg/m² (P < .001), and mean HbA1c decreased to 5.7 ± 0.9% (P < .001). Thirteen patients (19.4%) continued to have DM, and 9 patients (13.4%) had prediabetes. Hypertension was present in 35 patients (53.7%), of whom 25 (71.4%) were receiving at least 1 antihypertensive medication.

LNSC levels remained abnormal in 16 patients (23.8%), although LNSC data were not available for 21 patients (31.3%). Of those, LNSC testing was not considered clinically indicated in some cases, such as patients on HC replacement for postoperative AI (n = 10) or patients with adrenal CS status postadrenalectomy (n = 3). The remaining 8 patients with missing LNSC data were on medical therapy (n = 4) or status post-TSS (n = 4).

Cushing QoL

Sixty-five patients (71 baseline to follow-up case pairs) completed the CushingQoL assessment. In the overall cohort, treatment resulted in significant improvements in mean QoL scores at all follow-up time points: mean change in G1 was 16.6 ± 18.6 (P < .001); G2, 19.1 ± 19.4 (P < .001); and G3, 16.6 ± 27.1 (P = .009) (Table 3, Fig. 2A). For longest available follow-up for each case, overall mean improvement was 18.2 ± 20.9 points (P < .001).

 

Score trajectory for (A) Cushing QoL, (B) BDI-II, (C) STAI-State, and (D) STAI-Trait in the overall cohort based on duration of follow-up, including patients with 2 follow-up visits. Significant improvements in mean scores were observed in all assessments and all follow-up time points except in group 3 STAI-State, noted with a gray line. Group 1: 6 months posttreatment, group 2: 12 to 18 months posttreatment, group 3: ≥ 24 months posttreatment.

Figure 2.

Score trajectory for (A) Cushing QoL, (B) BDI-II, (C) STAI-State, and (D) STAI-Trait in the overall cohort based on duration of follow-up, including patients with 2 follow-up visits. Significant improvements in mean scores were observed in all assessments and all follow-up time points except in group 3 STAI-State, noted with a gray line. Group 1: 6 months posttreatment, group 2: 12 to 18 months posttreatment, group 3: ≥ 24 months posttreatment.

Abbreviations: BDI-II, Beck Depression Inventory-II; QoL, quality of life; STAI, State-Trait Anxiety Inventory.

 
Table 3.

Cushing QoL scores at baseline, follow-up visit, and mean score change in each time-based group for total cohort, patients who had TSS and patients on medical therapy

Category Subgroup n Baseline mean Follow-up visit mean Mean change SD (change) P-value
Total cohort Longest follow-up 71 42.4 60.6 18.2 20.9 <.001
Group 1 45 40.6 57.2 16.6 18.6 <.001
Group 2 30 43.5 62.6 19.1 19.4 <.001
Group 3 23 41.2 57.9 16.6 27.1 .009
TSS Longest follow-up 42 40.0 59.9 20.0 18.5 <.001
Group 1 29 40.2 57.0 16.8 19.1 <.001
Group 2 21 41.4 61.9 20.4 15.8 <.001
Group 3 9 29.0 48.7 19.7 24.9 .045
Medical therapy Longest follow-up 19 46.3 58.4 12.1 26.2 .059
Group 1 9 44.6 56.7 12.1 18.5 .086
Group 2 7 40.9 57.1 16.3 31.4 .219
Group 3 10 56.0 62.0 6.0 27.9 .513

Abbreviations: QoL, quality of life; TSS, transsphenoidal surgery.

In the subanalysis by treatment strategy, 42 patients who completed the Cushing QoL achieved surgical remission and 19 patients were controlled on medical therapy. In the surgical cohort, improvement in scores were noted across all time groups with a mean score increase of 20.0 ± 18.5 points from baseline to the longest available follow-up (P < .001) (Figs. 3A and 4A). Among these patients, 15 had 2 follow-up visits; between them the mean score further increased by 9.6 ± 14.8 points, indicating significant QoL improvement >6 months postsurgery (P  = .025). In contrast, patients under medical control at follow-up showed a mean improvement of 12.1 ± 26.2 points from baseline to the longest follow-up, which did not reach statistical significance (n = 19; P  = .059) (Table 3, Figs. 3A and 4A).

 

Mean score change in total cohort, patients after transsphenoidal surgery, and patients on medical therapy based on duration of follow-up: (A) Cushing QoL, (B) BDI-II, (C) STAI-State, (D) STAI-Trait. Direct comparison between the 2 treatment modalities was performed only in the longest available follow-up visit for each patient. Caps represent SEM. Only P-values ≤ .05 are displayed.

Figure 3.

Mean score change in total cohort, patients after transsphenoidal surgery, and patients on medical therapy based on duration of follow-up: (A) Cushing QoL, (B) BDI-II, (C) STAI-State, (D) STAI-Trait. Direct comparison between the 2 treatment modalities was performed only in the longest available follow-up visit for each patient. Caps represent SEM. Only P-values ≤ .05 are displayed.

Abbreviations: BDI-II, Beck Depression Inventory-II; QoL, quality of life; STAI, State-Trait Anxiety Inventory.

 

Mean scores at baseline and longest follow-up in total cohort, patients after transsphenoidal surgery, and patients on medical therapy for (A) Cushing QoL, (B) BDI-II, (C) STAI-State, (D) STAI-Trait. Caps represent SEM. Asterisks (*) indicate significant change from baseline to follow-up (P ≤ .05) and brackets significant differences between the 2 treatment modalities at the longest follow-up visit (P ≤ .05).

Figure 4.

Mean scores at baseline and longest follow-up in total cohort, patients after transsphenoidal surgery, and patients on medical therapy for (A) Cushing QoL, (B) BDI-II, (C) STAI-State, (D) STAI-Trait. Caps represent SEM. Asterisks (*) indicate significant change from baseline to follow-up (P ≤ .05) and brackets significant differences between the 2 treatment modalities at the longest follow-up visit (P ≤ .05).

Abbreviations: BDI-II, Beck Depression Inventory-II; QoL, quality of life; STAI, State-Trait Anxiety Inventory.

MID achievement and predictors of improvement

In the overall cohort, CushingQoL MID was achieved in 42 of the 65 patients (64.6%) (Fig. 5). When stratified by follow-up duration, MID achievement rates were 60.8% in G1 (n = 45), 70.0% in G2 (n = 30), and 60.9% (n = 23) in G3.

 

MID achievement rates for all patient-reported outcomes at most recent follow-up.

Figure 5.

MID achievement rates for all patient-reported outcomes at most recent follow-up.

Abbreviations: MID, minimal important difference.

Males (n = 11) improved more than female patients (n = 54) (27.8 ± 13.0 vs 15.5 ± 21.9; P  = .020) and achieved the MID more frequently (90.9% vs 59.3%; P  = .045). Even though they presented with lower baseline scores compared to females (33.2 ± 16.3 vs 44.3 ± 20.7), that difference was not significant (P  = .117).

Score change differed by BMI category, using as cut-off the baseline mean of our cohort (≤33.2 vs >33.2 kg/m²): patients with lower BMI (n = 34) improved considerably more than those with higher BMI (n = 31) (median score change: 26 vs 11; P = .023). Likewise, MID achievement was more common in the low-BMI group (76.5% vs 51.6%; P = .036).

Patients presenting with recurrent disease at baseline (n = 16) reported better baseline QoL than those with primary disease (n = 49) (51.6 ± 19.5 vs 39.5 ± 20.9; P = .046), and their mean improvement following treatment was smaller (7.2 ± 21.0 vs 21.0 ± 19.8; P = .022). Only 43.8% of recurrent cases achieved the MID compared to 71.4% of primary cases (P = .044).

Patients reporting symptom duration ≥3 years prior to diagnosis (n = 29) were less likely to achieve the MID compared to those with shorter symptom duration (n = 35) (48.3% vs 66.7%; P = .008).

Patients with at least 1 abnormal LNSC (n = 15) value at follow-up were less likely to meet MID compared to those with normal LNSC values (n = 28) (33.3% vs 75.0%; P = .008). Similarly, patients requiring HC replacement (after their first TSS or unilateral adrenalectomy for adrenal CS) for >6 months (n = 22) were more likely to achieve MID than those requiring ≤6 months (n = 30) (81.8% vs 50.0%; P = .019).

MID achievement rates between the TSS and medical-therapy groups differed (71.4% vs 47.4%) but did not reach significance (P = .070).

Baseline 24 hours UFC was inversely correlated with baseline CushingQoL score (ρ = −0.3; P = .035), indicating a relationship between biochemical and symptomatic disease severity.

BDI-II

Fifty-six patients (60 case pairs) were included in this subgroup. In the overall cohort, improvements in BDI-II score were seen at all follow-up time points: mean change in G1 was 4.7 ± 9.2 (P = .004); in G2, 7.7 ± 7.3 (P  < .001); and in G3, 7.6 ± 10.6 (P = .008). In the overall cohort, mean improvement from baseline to the longest follow-up was 6.8 ± 8.6 points (P  < .001) (Table 4, Fig. 2B). Of note, a significant 7.3-point improvement was noted between follow-up G1 (6 months) and follow-up G2 (12 months) (n = 11, P = .025), indicating continued improvement in depressive symptoms over time after treatment.

 
Table 4.

BDI-II scores at baseline, follow-up visit, and mean score change in each time-based group for total cohort, patients who had TSS and patients on medical therapy

Category Subgroup n Baseline mean Follow-up visit mean Mean change SD (change) P-value
Total cohort Longest follow-up 60 15.7 8.9 6.8 8.6 <.001
Group 1 37 17.0 12.2 4.7 9.2 .004
Group 2 26 15.2 7.5 7.7 7.3 <.001
Group 3 18 15.9 8.3 7.6 10.6 .008
TSS Longest follow-up 32 17.1 8.2 8.8 8.1 <.001
Group 1 22 18.6 13.6 5.0 10.9 .043
Group 2 17 14.7 6.7 8.0 8.1 <.001
Group 3 6 20.5 8.3 12.2 4.7 .001
Medical therapy Longest follow-up 18 14.4 11.0 3.4 9.9 .159
Group 1 8 14.6 11.0 3.6 6.7 .171
Group 2 6 18.3 10.8 7.5 7.1 .049
Group 3 9 11.8 8.8 3.0 13.3 .517

Abbreviations: BDI-II, Beck Depression Inventory-II; TSS, transsphenoidal surgery.

Among the 32 patients who underwent TSS, improvements were noted across all follow-up time groups, with mean scores decreasing from 17.1 ± 10.9 to 8.2 ± 7.0 at the longest follow-up (P  < .001). In contrast, the 18 patients treated medically did not experience a significant change (P = .159). Improvement following TSS was significantly greater than with medical therapy at longest follow-up for each case (8.8 ± 8.1 vs 3.4 ± 9.9; P = .043) (Figs. 3B and 4B).

MID achievement and improvement predictors

Thirty-eight patients (67.9%) achieved MID by their longest follow-up (Fig. 5). Twenty-nine (51.8%) patients had baseline scores ≥14 points, indicating mild or moderate depression, and 23 (79.3%) of these patients met the MID. By follow-up duration, overall MID achievement rates were 56.8% in G1 (n = 37), 76.9% in G2 (n = 26), and 72.2% in G3 (n = 18).

By treatment approach, MID was met by 75.0% of patients who had TSS (n = 32) and 38.9% of patients on medication (n = 18) (P = .012). All patients who underwent BLA (n = 4) or RT (n = 1) and 5 out of 6 patients treated for adrenal CS achieved MID.

Patients with recurrent and primary disease did not differ in terms of baseline score (P = .267). However, those with recurrent disease were less likely to achieve MID (42.9% vs 76.2%; n = 14 vs 75.6%; n = 42, P = .021).

Symptom duration prior to diagnosis was inversely correlated with BDI-II score change (ρ = −0.33, P = .016). Patients experiencing symptoms for ≥3 years (n = 24) exhibited lower MID achievement rates compared to those with shorter symptom duration (n = 31) (50.0% vs 83.9%; P = .007).

Patients with normal LNSC at follow-up had higher MID achievement rates (81.5%; n = 27 vs 45.5%; n = 11, P = .026).

STAI

STAI-S

Fifty-six patients (60 case pairs) completed the STAI-State questionnaire. All follow-up time groups exhibited improvements, although in G3 the score decrease did not reach significance. In the overall cohort, mean scores declined from 44.8 ± 14.0 to 35.3 ± 11.2 at the longest follow-up (P < .001) (Table 5).

 
Table 5.

STAI scores at baseline, follow-up visit, and mean score change in total cohort, patients who had TSS and patients on medical therapy

Outcome Category Subgroup n Baseline mean Follow-up visit mean Mean change SD (change) P-value
STAI-State Total cohort Longest follow-up 60 44.8 35.3 9.6 12.5 <.001
Group 1 40 45.9 36.6 9.3 12.3 <.001
Group 2 25 46.2 35.3 10.8 10.8 <.001
Group 3 17 42.4 36.1 6.3 13.8 .078
TSS Longest follow-up 33 44.4 34.3 10.1 12.3 <.001
Group 1 24 44.4 35.8 8.6 11.9 .002
Group 2 16 43.7 33.9 9.8 11.9 .005
Group 3 7 46.0 37.9 8.1 12.1 .126
Medical therapy Longest follow-up 17 47.2 37.4 9.8 14.7 .014
Group 1 9 50.9 37.2 13.7 13.7 .017
Group 2 5 56.4 39.8 16.6 8.4 .012
Group 3 8 36.3 34.6 2.0 14.9 .715
STAI-Trait Total cohort Longest follow-up 58 46.0 37.3 8.6 12.6 <.001
Group 1 36 47.9 40.3 7.6 12.0 <.001
Group 2 26 45.7 36.0 9.6 10.9 <.001
Group 3 16 46.7 36.9 9.8 13.2 .010
TSS Longest follow-up 31 47.5 36.7 10.7 12.2 <.001
Group 1 22 47.9 40.6 7.3 11.5 .008
Group 2 16 46.3 35.9 10.4 11.4 .002
Group 3 6 54.0 37.8 16.2 7.5 .003
Medical therapy Longest follow-up 18 45.1 38.8 6.2 13.4 .065
Group 1 8 49.5 39.8 9.8 14.0 .089
Group 2 6 47.5 36.2 11.3 10.9 .052
Group 3 8 39.3 37.5 1.8 12.7 .709

Abbreviations: STAI, State-Trait Anxiety Inventory; TSS, transsphenoidal surgery.

By treatment modality, state anxiety improved in both the TSS group (10.1 ± 12.3; n = 33; P < .001) and patients on medical therapy (9.8 ± 14.7; n = 17; P = .014) (Figs. 3C and 4C).

MID achievement and improvement predictors

Overall, 30 of 56 (53.5%) patients achieved MID in STAI-State at their longest follow-up visit (Fig. 5). By follow-up duration, MID achievement rates were 52.5% in G1 (n = 40), 56.1% in G2 (n = 25), and 64.7% in G3 (n = 17).

A negative correlation was observed between STAI-S score change and baseline age (ρ = −0.3, P = .029). Patients >40 years old at baseline (n = 29), improved less than younger patients (n = 27) [median score change: 5 vs 13 (P = .017)] and were less likely to meet the MID, with results approaching statistical significance (41.4% vs 66.7%, P = .058).

STAI-T

Fifty-three patients (58 case pairs) were evaluated. In the overall cohort, mean score change from baseline to longest follow-up was 8.6 ± 12.6 points (P < .001). In time-based subgroups the following score reductions were noted: G1: 7.6 ± 12.0 (P < .001), G2: 9.6 ± 10.9 (P < .001), G3: 9.8 ± 13.2 (P = .010) (Fig. 2D). Among patients treated with TSS (n = 31), significant improvement was seen in every subgroup. Patients receiving medical therapy (n = 18) showed numerical but not statistically significant improvement (P = .065) (Table 5, Figs. 3D and 4D).

MID achievement and improvement predictors

STAI-Trait MID was achieved by 28 (52.8%) patients at the longest follow-up (Fig. 5). By follow-up duration, MID achievement rates were 44.4% in G1, 53.8% in G2, and 68.8% in G3.

Patients ≤40 years at baseline (n = 26) improved more than those aged >40 years (n = 27), with results approaching significance [median score change: 14 vs 4 (P = .060)].

Patients with ≥2 Follow-up Visits

Twenty-eight patients had multiple follow-up visits; we stratified by follow-up duration (<2 years vs ≥2 years) [Table S1 (30)].

Cushing QoL

Significant improvements were noted in all groups with pairwise comparisons revealing higher scores in both first and second follow-up, with the mean score changing by 14.9 (P = .002) and 21.5 (P < .001) points, respectively, in total cohort.

BDI-II

Although the overall trajectory demonstrated significant improvement, pairwise comparisons showed no significant changes between baseline and first follow-up. Improvement was noted between baseline and the second follow-up visit (P < .001) and between the 2 treated visits (P = .021) (Table 6).

 
Table 6.

BDI-II mean scores and pairwise comparisons in patients with 2 follow-up visits

Comparison Mean score A Mean score B Mean difference P-value
Baseline vs follow-up 1 16.9 13.0 4.846 .200
Baseline vs follow-up 2 16.9 7.1 9.731 <.001
Follow-up 1 vs follow-up 2 13.0 7.1 4.885 .021

Abbreviations: BDI-II, Beck Depression Inventory-II.

STAI-S

Overall, the mean score decreased from 45.9 ± 13.0 at baseline to 38.3 ± 12.4 at the first follow-up and to 36.1 ± 10.9 at the second follow-up (P = .005). In cases with follow-up ≥2 years (n = 13), the score trajectory did not change significantly from baseline (P = .187). In contrast, patients with total follow-up <2 years (n = 11) exhibited significant improvement (P = .008).

STAI-T

Overall, the mean score decreased from 49.2 ± 9.0 at baseline to 39.8 ± 11.6 at first follow-up and further to 36.4 ± 10.5 at second follow-up (P < .001). Significant improvement noted from baseline to both follow-up visits in both subgroups (P < .001).

Regression Analyses for Predictors of Change

In all measurements, after controlling for age and sex, baseline score was an independent predictor of greater change (P < .001) (Table 7). Patients with more impaired QoL, or severe depression and anxiety at baseline, had more room for improvement.

 
Table 7.

Predictors of mean score change from baseline to most recent follow-up of each patient in univariable and multivariable linear regression analysis

Outcome Parameter Univariable analysis Multivariable analysis
Estimate SE P-value Estimate SE P-value
Cushing QoL score change Baseline score −0.50 0.11 <.001 −0.47 0.11 <.001
Baseline age −0.05 0.20 .797 −0.04 0.19 .825
Male sex 12.11 6.83 .081 7.49 6.68 .267
Baseline age ≤40 (vs >40) −3.43 5.23 .515 −4.90 4.89 .321
Normal LNSC (vs abnormal) −19.98 6.4 .004 −19.39 5.26 .001
HC replacement >6 months (vs ≤6 months) 10.06 5.90 .095 12.35 4.96 .016
Primary disease at baseline (vs recurrent) −13.19 5.86 .028 −6.63 5.60 .241
Baseline BMI ≤33.2 kg/m2 (vs >33.2 kg/m2) −8.72 5.1 .095 −6.53 4.71 .171
Symptom duration ❤ years (vs ≥3 years) −4.60 5.25 .384 −4.55 4.70 .337
Treatment (TSS vs medical therapy) −7.87 5.8 .185 −4.23 5.41 .473
BDI-II score change Baseline score 0.57 0.09 <.001 0.58 0.09 <.001
Baseline age −0.08 0.09 .402 0.02 0.08 .797
Male sex −0.59 3.07 .848 0.80 2.53 .752
Baseline age ≤40 (vs >40) −3.96 4.82 .429 −0.52 2.02 .800
Normal LNSC (vs abnormal) −3.01 3.06 .332 −3.27 1.87 .090
HC replacement >6 months (vs ≤6 months) 0.06 2.577 .980 2.33 1.90 .226
Primary disease at baseline (vs recurrent) −4.76 2.63 .076 −2.66 2.17 .224
Baseline BMI ≤33.2 kg/m2 vs >33.2 kg/m2 −3.79 2.29 .104 −1.41 1.90 .462
Symptom duration ❤ years (vs ≥3 years) −5.61 2.23 .015 −3.49 1.78 .055
Treatment (TSS vs medical therapy) −5.46 2.60 .041 −3.94 2.02 .057
STAI-State score change Baseline score 0.57 0.09 <.001 0.56 0.09 <.001
Baseline age −0.22 0.13 .104 −0.11 0.12 .338
Male sex −5.70 4.37 .197 −4.39 3.69 .239
Baseline age ≤40 (vs >40) −5.94 3.30 .078 −3.75 2.73 .175
Normal LNSC (vs abnormal) −2.15 3.95 .589 −4.47 2.89 .131
HC replacement >6 months (vs ≤6 months) 0.72 3.45 .836 4.42 2.81 .123
Primary disease at baseline (vs recurrent) 2.41 3.91 .743 2.14 2.91 .465
Baseline BMI ≤33.2 kg/m2 (vs >33.2 kg/m2) −2.36 3.38 .488 −0.93 2.56 .716
Symptom duration ❤ years (vs ≥3 years) −5.67 3.33 .095 −3.26 2.46 .192
Treatment (TSS vs medical therapy) −1.50 3.91 .970 −2.77 2.97 .355
STAI-Trait score change Baseline score 0.58 0.11 <.001 0.56 0.12 <.001
Baseline age −0.20 0.13 .128 −0.07 0.11 .562
Male sex −3.09 4.57 .502 −0.83 4.13 .841
Baseline age ≤40 (vs >40) −5.45 3.36 .111 −2.55 3.03 .405
Normal LNSC (vs abnormal) −6.52 4.23 .133 −6.74 3.44 .059
HC replacement >6 months (vs ≤6 months) 4.63 3.52 .195 7.11 2.87 .018
Primary disease at baseline (vs recurrent) −2.07 3.90 .597 −0.34 3.42 .921
Baseline BMI ≤33.2 kg/m2 (vs >33.2 kg/m2) −4.95 3.38 .150 −2.59 3.00 .393
Symptom duration ❤ years (vs ≥3 years) −5.78 3.37 .093 −4.35 2.80 .127
Treatment (TSS vs medical therapy) −4.49 3.74 .236 −3.39 3.11 .281

Each predictor in multivariable analysis was separately evaluated, adjusting for baseline age, sex, and baseline score. In models exploring baseline age <40 years as a categorical variable, continuous baseline age was not included in the multivariable model. Statistically significant results (P ≤ .05) are indicated in bold.

Abbreviations: BDI-II, Beck Depression Inventory-II; BMI, body mass index; HC, hydrocortisone; LNSC, late-night salivary cortisol; QoL, quality of life; STAI, State-Trait Anxiety Inventory; TSS, transsphenoidal surgery.

Cushing QoL

Normal LNSC at follow-up and >6 months of postoperative HC replacement were predictors of QoL score improvement and MID achievement even after adjustment for baseline score, age, and sex. Lower baseline BMI and male sex, although significant in univariable analysis, were no longer significant in the multivariable linear model. However, a BMI < 33.2 kg/m² (P = .034) and symptom duration ❤ years prior to diagnosis (P = .005) remained statistically significant predictors of reaching the MID in the multivariable logistic model (Table 8, Fig. 6). To determine if treatment modality modified the effect of LNSC, we built a model including baseline QoL score, age, sex, follow-up LNSC, and treatment type (TSS vs medical therapy). In this multivariable model, normal LNSC remained a significant predictor of improvement (P = .023).

 

MID achievement predictors after multivariable analysis for (A) Cushing QoL, (B) BDI-II, (C) STAI-State. Each predictor was analyzed in a separate logistic regression model after adjustment for baseline score, age, and sex. Predictors for trait anxiety are not shown, as a longer duration of postoperative HC replacement was a significant predictor only in the linear multivariable regression model.

Figure 6.

MID achievement predictors after multivariable analysis for (A) Cushing QoL, (B) BDI-II, (C) STAI-State. Each predictor was analyzed in a separate logistic regression model after adjustment for baseline score, age, and sex. Predictors for trait anxiety are not shown, as a longer duration of postoperative HC replacement was a significant predictor only in the linear multivariable regression model.

Abbreviations: BDI-II, Beck Depression Inventory-II; HC, hydrocortisone; LNSC, late-night salivary cortisol; QoL, quality of life; STAI, State-Trait Anxiety Inventory; TSS, transsphenoidal surgery.

 
Table 8.

Predictors of MID achievement from baseline to most recent follow-up of each patient in univariable and multivariable logistic regression models

Outcome Parameter Univariable analysis Multivariable analysis
Estimate SE P-value Estimate SE P-value
Cushing QoL MID achievement Baseline score 0.94 0.02 <.001 0.94 0.02 <.001
Baseline age 1.01 0.02 .548 1.02 0.03 .410
Male sex 6.89 1.09 .076 3.82 1.16 .249
Baseline age ≤40 (vs >40) 1.01 0.52 .987 1.27 0.62 .704
Normal LNSC (vs abnormal) 6.00 0.70 .011 22.82 1.17 .007
HC replacement >6 months (vs ≤6 months) 4.50 0.66 .023 14.49 0.99 .007
Primary disease at baseline (vs recurrent) 3.21 0.60 .050 1.78 0.68 .400
Baseline BMI ≤33.2 kg/m2 (vs >33.2 kg/m2) 3.05 0.54 .039 4.33 0.69 .034
Symptom duration ❤ years (vs ≥3 years) 4.29 0.56 .010 9.07 0.78 .005
Treatment (TSS vs medical therapy) 2.79 0.57 .074 2.36 0.68 .209
BDI-II MID achievement Baseline score 1.08 0.04 .064 1.08 0.04 .042
Baseline age 1.02 0.02 .510 1.01 0.03 .613
Male sex 5.28 1.10 .130 5.76 1.14 .126
Baseline age ≤40 (vs >40) 1.11 0.57 .854 1.05 0.63 .937
Normal LNSC (vs abnormal) 5.28 0.78 .033 14.86 1.25 .030
HC replacement >6 months (vs ≤6 months) 2.00 0.65 .288 2.32 0.71 .236
Primary disease at baseline (vs recurrent) 4.27 0.65 .026 2.67 0.71 .165
Baseline BMI ≤33.2 kg/m2 (vs >33.2 kg/m2) 1.94 0.58 .255 1.55 0.66 .504
Symptom duration < 3 years (vs ≥3 years) 5.20 0.64 .010 5.74 0.70 .012
Treatment (TSS vs medical therapy) 4.71 0.63 .014 4.19 0.69 .039
STAI-State MID achievement Baseline score 1.17 0.04 <.001 1.19 0.05 <.001
Baseline age 0.97 0.02 .241 0.96 0.03 .261
Male sex 1.95 0.71 .347 3.17 1.00 .249
Baseline age ≤40 (vs >40) 2.83 0.56 .061 5.87 0.89 .048
Normal LNSC (vs abnormal) 2.02 0.73 .337 2.41 1.04 .396
HC replacement >6 months (vs ≤6 months) 0.94 0.59 .943 2.66 0.97 .313
Primary disease at baseline (vs recurrent) 1.21 0.62 .757 2.15 0.92 .408
Baseline BMI ≤33.2 kg/m2 (vs >33.2 kg/m2) 2.05 0.54 .189 1.57 0.82 .584
Symptom duration < 3 years (vs ≥3 years) 1.39 0.55 .52 0.98 0.77 .980
Treatment (TSS vs medical therapy) 1.95 0.62 .279 1.44 0.78 .634
STAI-Trait MID achievement Baseline score 1.17 0.05 <.001 1.17 0.05 <.001
Baseline age 0.98 0.02 .295 0.97 0.03 .342
Male sex 2.33 0.75 .257 4.16 1.02 .161
Baseline age ≤40 (vs >40) 2.12 0.56 .175 2.32 0.76 .265
Normal LNSC (vs abnormal) 1.78 0.71 .416 1.48 0.96 .686
HC replacement >6 months (vs ≤6 months) 1.58 0.60 .450 4.21 0.95 .130
Primary disease at baseline (vs recurrent) 2.45 0.61 .138 2.06 0.90 .421
Baseline BMI ≤33.2 kg/m2 (vs >33.2 kg/m2) 1.98 0.54 .202 1.11 0.79 .891
Symptom duration < 3 years (vs ≥3 years) 1.09 0.53 .866 0.99 0.71 .984
Treatment (TSS vs medical therapy) 1.39 0.60 .585 1.18 0.82 .839

Each predictor in multivariable analysis was separately evaluated, adjusting for baseline age, sex and baseline score. In models exploring baseline age <40 years as a categorical variable, continuous baseline age was not included in the multivariable model. Statistically significant results (P ≤ .05) are indicated in bold.

Abbreviations: BDI-II, Beck Depression Inventory-II; BMI, body mass index; HC, hydrocortisone; LNSC, late-night salivary cortisol; MID, minimal important difference; QoL, quality of life; STAI, State-Trait Anxiety Inventory; TSS, transsphenoidal surgery.

BDI-II

Symptom duration ❤ years (P = .012), normal LNSC at follow-up (P = .030), and TSS (P = .039) instead of medical therapy (for CD) were statistically significant predictors of MID achievement in the multivariable logistic models even after adjusting for age, sex, and baseline score (Table 8, Fig. 6).

STAI-S

In the multivariable logistic model adjusted for sex and baseline score, age <40 predicted higher odds of MID achievement (P = .041) (Table 8, Fig. 6).

STAI-T

After adjustments for sex and baseline score, age group <40 was no longer a predictor of improvement. Although nonsignificant in univariable screening, duration of postoperative HC replacement >6 months emerged as a significant predictor of score change, though not MID achievement, after adjusting for age, sex, and baseline score (Tables 7 and 8).

Discussion

In a clinical practice cohort of patients with CS followed prospectively before and over time up to 11.5 years after surgical remission and/or biochemical control from medical treatment, we identified significant improvements in mean QoL, depression, and anxiety scores in the overall cohort, but only half of patients achieved clinically meaningful improvements in anxiety, as assessed by MID, and about two-thirds of the cohort achieved clinically meaningful improvements in QoL and depression at their most recent follow-up. When assessed by treatment strategy, surgery resulted in statistically significant improvements in all 3 measures, whereas medical therapy resulted in statistically significant improvements in state anxiety but not QoL or depression. These findings may be impacted by the smaller cohort size of the medically treated patients and more complex treatment journeys in the medically vs surgically treated patients. Overall, in this cohort of treated, biochemically controlled patients, several predictors of improvements were identified, including age, baseline BMI, duration of symptoms prior to treatment, duration of HC requirement after surgery, and LNSC normalization with treatment.

PRO studies in CS have shown that patients with CS are at risk for mood disorders and impaired QoL at diagnosis and that improvement posttreatment is often partial, delayed, or inconsistent, even after biochemical remission (3-12). The most recent prospective study confirmed persistent deficits in QoL and depressive symptoms up to 1 year postsurgery, with mean BDI-II scores remaining in the clinically significant range (9). As for anxiety, a prospective study reported high baseline anxiety in patients with CD, and, although it improved after surgery, a proportion continued to experience anxiety up to 1 year posttreatment (14). Neuroimaging supports a biological basis for these symptoms, with brain abnormalities (hippocampal atrophy, cortical thinning, white matter damage) seen after biochemical cure possibly explaining the long-term emotional and cognitive deficits in some patients (12, 15). As for previously reported predictors of improvement, male sex, lower BMI at follow-up (4, 31, 32), LNSC normalization (17), and shorter duration of cortisol exposure (32, 33) emerged as independent predictors of better QoL. Persistent hormone deficits or arginine vasopressin deficiency were related to worse depression (9) while increased age and male sex predicted less anxiety (31). While some studies suggest that hypopituitarism and HC replacement are associated with poorer outcomes (11, 34), others found no significant difference (35). Limitations of these studies include the cross-sectional design (4, 31-36), small cohort sizes (9), and lack of long-term follow-up >12 months (37), especially in the setting of clinical trials (17).

In our study, QoL, depression, and anxiety improved following treatment, but the patterns varied by domain and follow-up duration.

As for QoL, interestingly, patients with recurrent disease showed better baseline QoL scores than those with primary disease, possibly due to posttreatment surveillance, resulting in earlier diagnosis at recurrence vs initial presentation. Although patients on medical therapy showed a trend toward improvement with treatment, results did not reach significance, potentially due to sample size or the increased (better) baseline scores in patients with recurrent disease and thus those receiving medical treatment. Most patients on medical therapy had persistent or recurrent disease and have experienced longer, more complex treatment journeys (as depicted in Fig. 1) compared to those in surgical remission, which also may impact QoL and mood outcomes. Notably, in patients with 2 follow-up visits, QoL continued to significantly improve 6 months posttreatment in those treated surgically but not in the total cohort.

Multivariable analysis revealed several predictors of QoL improvement after treatment. LNSC normalization was independently associated with approximately 20 times higher odds of achieving the MID, indicating the clinical importance of recovery of cortisol circadian rhythm for treated CS patients and the need for further work to identify medical therapies and regimens that can facilitate this. Postoperative HC replacement for more than 6 months after surgery (indicating a longer hypothalamic-pituitary-adrenal axis recovery) was also associated with greater QoL improvement. This finding complements prior work showing an association between duration of postoperative HC replacement and long-term remission (38, 39). Lower baseline BMI and shorter symptom duration were predictive of MID achievement, though not of mean score change.

As for depression, patients with 2 follow-ups had a distinct pattern: no significant change between baseline and first follow-up but significant improvement between the 2 follow-up visits. This suggests that depression may take longer to improve, with more evident change >6 months after biochemical control, which contrasts prior work suggesting that anxiety takes longer than depression to improve (14). The delayed trajectory could reflect the structural brain changes seen in CS even in remission, which are partially reversible (12, 40). Our data showed that symptom duration > 3 years prior to diagnosis reduced MID achievement, consistent with the literature linking diagnostic delay to persistent depression (33). A normal follow-up LNSC was associated with approximately 15 times higher odds of achieving the MID after adjustment, again emphasizing the need to attempt LNSC normalization while on medical therapy (9, 17).

As for anxiety, to date, no prospective study has assessed anxiety longitudinally using STAI, the gold standard for measuring and differentiating between trait and state anxiety (29). Our results confirm that anxiety improves after treatment; however, state and trait show different patterns. State anxiety was the only domain overall to improve significantly in the medical therapy group, while trait anxiety showed only a trend. Although age <40 predicted greater anxiety improvements in both, this remained significant only for state anxiety after adjustment in the logistic model. Trait anxiety improvements were predicted by longer postoperative HC replacement in the linear multivariable model, again suggesting that a shorter recovery time of the HPA axis may be an early indicator for identifying patients who require a closer follow-up. A normal LNSC at follow-up approached significance in the multivariable linear model, suggesting the importance of circadian rhythm recovery in trait anxiety improvement as well.

Across all measures, we found no baseline or outcome differences between pituitary and adrenal CS or between those on or off HC replacement at their last follow-up. Of note, our cohort was predominantly CD patients, and the small number of adrenal CS patients may limit the ability to detect a difference in the 2 cohorts.

Overall, discrepancies between mean change and MID achievement, as reflected in the linear and logistic models, respectively, highlight the importance of reporting both metrics when available, as they may capture different but clinically useful predictors.

We also observed differences between score change and MID achievement across different time groups within the same questionnaire. In STAI-State, G2 (12-18 months since most recent treatment) had greater score reductions than G3 (24 months or more posttreatment)—though change in G3 was nearly significant. However, a higher proportion of patients in G3 achieved MID. Looking at our data, G3 had the highest SD of mean change, indicating greater heterogeneity in treatment response, likely due to broader range of follow-up duration or higher medical therapy rates among patients: 45.5% (n = 10) in G3 vs 22.6% (n = 6) in G2% and 20% (n = 8) in G1. This variability in state anxiety is reflected in the subgroup of patients with 2 follow-up visits: those followed for >2 years showed no significant improvement, while those with <2 years did. Differential responses to long-term medical therapy, higher rates of loss to follow-up among postsurgical patients, or the negative impact of time on state anxiety symptoms may explain this. For BDI-II we used a percentage-based MID, which likely contributed to greater alignment with mean changes, and accounted for individual variability and baseline severity, factors especially relevant when applying generic tools in disease-specific contexts.

Of note, in the cohort overall, the mean follow-up score was within the normal range for depression (<14 for BDI-II) and anxiety (<40 for STAI) (41). This is an encouraging finding that, on average, patients with treated CS may have rates of depression and anxiety that are not clinically significant. Nevertheless, as shown in Table 2, rates of antidepressant, anxiolytic, pain, and sleep medication use did not decrease with treatment but instead were stable or increased numerically, although they were not statistically significant. Similarly, case-control studies have reported higher depression and anxiety levels in patients with CS in remission when compared to healthy controls, even if the mean scores were within the normal range for both groups (15, 42). Whether this difference is clinically significant still remains inconclusive. Taken together, these results emphasize the importance of multidisciplinary pituitary centers that integrate formal psychological services, including psychiatric care and social work support, to monitor and promote long-term mental health in this population.

Inclusion of both surgically and medically treated patients may be considered a limitation to the study, since it introduces heterogeneity in the cohort. However, including patients undergoing a range of treatments allows for analysis of CS cohorts as seen in a real-world practice rather than a controlled clinical trial setting, thus providing clinically valuable information. Another limitation of the study is the use of clinically available, rather than centralized, hormone assays, again introducing variability in our data. As this cohort included patients treated at our center, their endocrine testing followed standard of care, which did not include sending samples to a centralized laboratory. The use of antidepressants in a minority of patients could potentially affect depression scores. However, this is an unavoidable reality in patients with CS, and their use was stable over time (14.9% at baseline vs 19.4% at follow-up, P = .49). Given our prospective study design, which captured each patient’s change relative to their own baseline, and adjustment for baseline scores in multivariable models, any confounding is likely limited.

Despite these limitations, our data contribute to the literature as the largest clinical practice cohort to date that prospectively characterizes QoL and mood disturbances in CS patients, before and over time after achieving biochemical control. By incorporating 3 longitudinal time points, we identified that the greatest improvements occur within the first 6 months for QoL and anxiety, while depression improves more gradually beyond that point. Another strength of our approach is the use of score change and MID as outcomes when exploring potential predictors of improvement and not remission score per se, enabling more precise tracking of each patient’s progress and supporting an individualized approach by accounting for baseline severity.

In summary, this prospective analysis of mood and Qol in a clinical practice cohort of patients with CS showed that effective treatment of hypercortisolism improves depression, anxiety, and QoL, but one-third to one-half of patients do not experience clinically meaningful improvements in these measures. We identified predictors of improvement that highlight the need for early detection of CS and treatment strategies that allow for recovery of cortisol circadian rhythm. Psychological recovery in CS is heterogeneous, domain-specific, and not always aligned with biochemical normalization. Our findings support a model of care that extends beyond endocrine remission, integrating psychosocial follow-up and individualized treatment.

Acknowledgments

We would like to thank the people with Cushing’s syndrome who contributed their valuable time to this research.

Funding

This research was funded by the National Institutes of Health/National Cancer Institute Support Grant P30 CA008748.

https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgaf598/8307075?login=false

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A Silent Invader: Asymptomatic Rhodococcus Infection Unmasked In a Patient With Ectopic ACTH-Dependent Cushing’s Syndrome

Posted on October 8, 2025 by MaryO

Introduction: Rhodococcus species, particularly Rhodococcus equi, are rare opportunistic pathogens that typically affect immunocompromised individuals. These infections usually present with respiratory or systemic symptoms and are often linked to environmental exposure. Asymptomatic Rhodococcus infections are exceedingly rare and pose unique diagnostic and therapeutic challenges.

Case description: We report the case of a 29-year-old male who presented with new-onset diabetes mellitus, resistant hypertension and significant weight gain. Physical examination revealed features consistent with Cushing’s syndrome. Biochemical evaluation confirmed ACTH-dependent hypercortisolism with an elevated plasma ACTH level, and a lack of suppression on high-dose dexamethasone testing; imaging identified a suspicious pulmonary nodule. Bronchoscopic biopsy revealed no malignancy, however cultures grew Rhodococcus species. The patient denied any respiratory symptoms or environmental exposure. Initial antibiotic therapy with ciprofloxacin and rifampin was started. Follow-up imaging showed rapid enlargement of the pulmonary mass, prompting surgical resection. Histopathology revealed malakoplakia, and repeat cultures again yielded Rhodococcus spp. Antibiotics were adjusted to azithromycin and rifampin, and the patient was started on ketoconazole to manage hypercortisolism.

Conclusion: This case highlights the importance of considering opportunistic infections such as Rhodococcus spp. in immunocompromised patients, even in the absence of symptoms. It underscores the diagnostic value of investigating incidental findings in such populations and illustrates the need for prompt, multidisciplinary management to prevent disease progression.

References

  • Prescott JF. Rhodococcus equi: an animal and human pathogen. Clin Microbiol Rev 1991;4:20–34. doi: 10.1128/CMR.4.1.20
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  • Weinstock DM, Brown AE. Rhodococcus equi: an emerging pathogen. Clin Infect Dis 2002;34:1379–1385. doi: 10.1086/340259
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  • Vázquez-Boland JA, Giguère S, Hapeshi A, MacArthur I, Anastasi E, Valero-Rello A. Rhodococcus equi: the many facets of a pathogenic actinomycete. Vet Microbiol 2013;167:9-33. doi: 10.1016/j.vetmic.2013.06.016
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  • Álvarez-Narváez S, Huber L, Giguère S, Hart KA, Berghaus RD, Sanchez S, et al. Epidemiology and Molecular Basis of Multidrug Resistance in Rhodococcus equi. Microbiol Mol Biol Rev 2021;85:e00011-21. doi: 10.1128/MMBR.00011-21
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  • Morton AC, Begg AP, Anderson GA, Takai S, Lämmler C, Browning GF. Epidemiology of Rhodococcus equi strains on Thoroughbred horse farms. Appl Environ Microbiol 2001;67:2167-2175. doi:10.1128/AEM.67.5.2167-2175.2001
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  • von Bargen K, Haas A. Molecular and infection biology of the horse pathogen Rhodococcus equi. FEMS Microbiol Rev 2009;33:870–891. doi: 10.1111/j.1574-6976.2009.00181.x
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  • Minnetti M, Hasenmajer V, Pofi R, Venneri MA, Alexandraki KI, Isidori AM. Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy. J Endocrinol 2020;246:R13–R31. doi: 10.1530/JOE-20-0066
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  • Whitacre CC, Reingold SC, O’Looney PA. A gender gap in autoimmunity. Science 1999;283:1277–1278. doi: 10.1126/science.283.5406.1277
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  • Yamshchikov AV, Schuetz A, Lyon GM. Rhodococcus equi infection. Lancet Infect Dis 2010;10:350–359. doi: 10.1016/S1473-3099(10)70068-2
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  • Marsh HP, Bowler IC, Watson CJ. Successful treatment of Rhodococcus equi pulmonary infection in a renal transplant recipient. Ann R Coll Surg Engl 2000;82:107-108.
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  • Ragnarsson O, Juhlin CC, Torpy DJ, Falhammar H. A clinical perspective on ectopic Cushing’s syndrome. Trends Endocrinol Metab 2024;35:347–360. doi: 10.1016/j.tem.2023.12.003
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From https://www.ejcrim.com/index.php/EJCRIM/article/view/5711

Filed under: Cushing's, Rare Diseases, symptoms | Tagged: , , , , , | Leave a comment »

Global Longitudinal Strain Reduction With Apical Sparing in Cushing Syndrome-Related Heart Failure With Preserved Ejection Fraction (HFpEF)

Posted on October 6, 2025 by MaryO

We describe a case of a 56-year-old woman with a history of recurrent pituitary adenoma, not well followed, and known comorbidities of coronary artery disease, hypertension, and type 2 diabetes mellitus. She arrived with severely high blood pressure and signs pointing to hypercortisolism.

Further evaluation revealed left ventricular hypertrophy, reduced global longitudinal strain, and preserved left ventricular ejection fraction, consistent with heart failure with preserved ejection fraction (HFpEF). Workup for amyloidosis was negative.

This case highlights that chronic hypercortisolism may cause pathophysiological changes in the heart, leading to HFpEF, and may induce myocardial fibrosis and impaired myocardial mechanics, producing an echocardiographic pattern that can mimic infiltrative cardiomyopathy. Recognition of this overlap is crucial to avoid misdiagnosis and to ensure timely endocrine and cardiovascular management.

Read here.

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

Ectopic Adrenocorticotropic Hormone (ACTH)-Dependent Cushing Syndrome Secondary to Olfactory Neuroblastoma

Posted on September 15, 2025 by MaryO

Abstract

Background/Objective

Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome is a rare paraneoplastic disorder caused by excessive cortisol production from nonpituitary tumors. Olfactory neuroblastoma (ONB), a rare neuroendocrine malignancy of the sinonasal cavity, is an exceedingly uncommon source of ectopic ACTH production, with fewer than 25 cases reported worldwide. This report presents a case of ACTH-dependent Cushing syndrome due to ONB, emphasizing the diagnostic complexity, multidisciplinary management, and favorable clinical outcomes.

Case Presentation

A 70-year-old male presented with progressive muscle weakness, facial rounding, weight gain, hypertension, hypokalemia, and recurrent epistaxis. Laboratory evaluation revealed marked hypercortisolism and elevated plasma ACTH. Imaging demonstrated an expansile ethmoid sinus mass. Inferior petrosal sinus sampling excluded a pituitary source of ACTH. Endoscopic biopsy confirmed Hyams grade 2 ONB with positive immunohistochemical staining for neuroendocrine markers and ACTH. The patient received preoperative cortisol-lowering therapy and underwent complete endoscopic tumor resection followed by adjuvant radiotherapy. Postoperative assessment showed biochemical remission, resolution of Cushingoid features, and eventual recovery of the hypothalamic–pituitary–adrenal axis.

Discussion

This case highlights the importance of a systematic diagnostic approach that includes biochemical testing, imaging, inferior petrosal sinus sampling, and histopathology to identify ectopic ACTH sources. It demonstrates the necessity of collaboration among endocrinology, otolaryngology, neurosurgery, radiology, and oncology teams in managing rare ACTH-secreting tumors.

Conclusion

Timely diagnosis and definitive surgical resection of ACTH-producing ONB, along with endocrine stabilization and adjuvant radiotherapy, can lead to endocrine remission and improved long-term outcomes.

Key words

cushing syndrome
ectopic ACTH syndrome
neuroendocrine tumor
olfactory neuroblastoma
paraneoplastic syndrome

Abbreviations

ACTH

adrenocorticotropic hormone

AM

morning (ante meridiem)

DDAVP

desmopressin acetate

DHEA-S

dehydroepiandrosterone sulfate

EAS

ectopic ACTH syndrome

ENT

otolaryngology

IPSS

inferior petrosal sinus sampling

ONB

olfactory neuroblastoma

UFC

urinary free cortisol

Highlights

  • •
    Rare case of ectopic adrenocorticotropic hormone syndrome secondary to olfactory neuroblastoma
  • •
    Diagnostic challenges highlighted, including nondiagnostic inferior petrosal sinus sampling results
  • •
    Multidisciplinary approach enabled complete tumor resection and hormonal remission
  • •
    Preoperative ketoconazole minimized perioperative cortisol-related morbidity
  • •
    Adjuvant radiotherapy optimized local control in intermediate-risk olfactory neuroblastoma

Clinical Relevance

This case emphasizes the importance of recognizing olfactory neuroblastoma as a rare source of ectopic adrenocorticotropic hormone production. It demonstrates the value of integrated biochemical, radiologic, surgical, and histopathologic strategies to achieve endocrine remission and prevent recurrence.

Introduction

Ectopic ACTH syndrome (EAS) is a rare paraneoplastic disorder resulting in ACTH-dependent hypercortisolism, which manifests clinically as Cushing syndrome. Although it accounts for approximately 10% to 15% of ACTH-dependent cases, EAS is most frequently caused by bronchial carcinoids, small cell lung carcinoma, and pancreatic neuroendocrine tumors.1,2 In contrast, olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma—a neuroendocrine malignancy of the upper nasal cavity—is a highly uncommon cause, with fewer than 1% of ONB cases associated with EAS.2,3
ONB arises from the olfactory epithelium and represents 2% to 3% of all sinonasal cancers.4,5 Its nonspecific presentation—ranging from nasal obstruction to epistaxis or anosmia—can delay diagnosis, and advanced tumors may invade adjacent structures such as the orbit or anterior cranial fossa.4,5 Histological overlap with other small round blue cell tumors necessitates immunohistochemical markers such as synaptophysin, chromogranin A, and S-100 for accurate identification.4,6 Factors such as age may influence tumor behavior, treatment selection, and prognosis.7
When ONB presents with ectopic ACTH secretion, the resulting hypercortisolism can lead to profound metabolic and cardiovascular complications.8,9 Due to its extreme rarity, this combination may not be initially suspected, delaying targeted therapy. This report presents a rare case of ACTH-dependent Cushing syndrome caused by ONB, highlighting the diagnostic complexity and need for multidisciplinary management.3,10

Case Presentation

A 70-year-old male presented with 6 weeks of progressively worsening generalized, proximal muscle weakness, intermittent headaches, recurrent nosebleeds, abdominal fullness, leg swelling, and an unexplained 20-pound (9.1 kg) weight gain.
His medical history includes asthma, benign prostatic hyperplasia, hyperlipidemia, and retained shrapnel in the neck from military service in Vietnam. He has no history of hypertension, diabetes, or smoking. His family history includes a father who suffered a myocardial infarction at 51 years old, a mother with rheumatoid arthritis and osteoporosis, and a maternal uncle with lupus. His current medications include rosuvastatin 5 mg daily, tamsulosin 0.4 mg daily, and an albuterol inhaler as needed.
On examination, his vital signs were notable for an elevated blood pressure of 171/84 mmHg (normal: <120/<80 mmHg), a temperature of 37.2 C (99 F) (normal: 36.1–37.2°C [97–99 F]), a heart rate of 91 bpm (normal: 60–100 bpm), a respiratory rate of 16 breaths per minute (normal: 12–20 breaths per minute), an oxygen saturation of 92% on room air (normal: ≥95%), and a weight of 78.9 kg (174 lb). Physical examination revealed a round plethoric face (“moon facies,”) a prominent dorsocervical fat pad (“buffalo hump,”) supraclavicular fullness, mild abdominal tenderness, violaceous striae across the abdomen, diffuse soft tissue swelling, and bilateral 2+ pitting edema in the lower extremities.

Diagnostic Assessment

Laboratory evaluation demonstrated severe hypokalemia (1.6 mEq/L [1.6 mmol/L]; normal: 3.5–5.0 mEq/L [3.5–5.0 mmol/L]) and marked fasting hyperglycemia (244.0 mg/dL [13.5 mmol/L]; normal: 70–99 mg/dL [3.9–5.5 mmol/L]), in addition to leukocytosis, hypochloremia, acute kidney injury, hypoproteinemia, and hypoalbuminemia.
Hormonal evaluation (Table 1) was consistent with ACTH-dependent hypercortisolism, characterized by elevated serum cortisol and ACTH concentrations, lack of suppression with dexamethasone, and suppressed dehydroepiandrosterone sulfate (DHEA-S). Aldosterone and plasma renin activity were within normal limits, effectively excluding primary hyperaldosteronism. Plasma free metanephrines and normetanephrines were also within reference ranges, ruling out pheochromocytoma. Repeat morning cortisol remained markedly elevated, and late-night salivary cortisol levels on 2 occasions were significantly above the reference range. Twenty-four-hour urinary free cortisol (UFC) was profoundly elevated on both collections. Following a 1 mg overnight dexamethasone suppression test, serum cortisol, ACTH, and dexamethasone levels confirmed a lack of cortisol suppression despite adequate dexamethasone absorption (Table 1). These results were consistent with ACTH-dependent Cushing syndrome.

Table 1. Hormone Panel Results

Test Value Normal Range
AM cortisol 29 μg/dL (800.11 nmol/L) (high) 3.7–19.4 μg/dL (102–535 nmol/L)
Repeated AM cortisol 26 μg/dL (717.34 nmol/L) (high) 3.7–19.4 μg/dL (102–535 nmol/L)
ACTH 250 pg/mL (30.03 pmol/L) (high) 10–60 pg/mL (2.2–13.2 pmol/L)
Plasma renin activity 1.2 ng/mL/h (1.2 μg/L/h) (normal) 0.2–4.0 ng/mL/h (0.2–4.0 μg/L/h)
DHEA-S 50 μg/dL (1.25 μmol/L) (low) 65–380 μg/dL (1.75–10.26 μmol/L)
Aldosterone, blood 4. 9 ng/dL (0.14 nmol/L) (normal) 4.0–31.0 ng/dL (110–860 pmol/L)
Plasma free metanephrines 0.34 nmol/L (0.034 μg/L) (normal) <0.50 nmol/L (<0.09 μg/L)
Plasma free normetanephrines 0.75 nmol/L (0.075 μg/L) (normal) <0.90 nmol/L (<0.16 μg/L)
Late-night salivary cortisol (1st) 0.27 μg/dL (7.45 nmol/L) (high) ≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
Late-night salivary cortisol (2nd) 0.36 μg/dL (9.93 nmol/L) (high) ≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
24-h urinary free cortisol (1st) 5880.0 μg/d (16 223 nmol/d) (high) ≤60.0 μg/d (≤165 nmol/d)
24-h urinary free cortisol (2nd) 4920.0 μg/d (13 576 nmol/d) (high) ≤60.0 μg/d (≤165 nmol/d)
AM cortisol level (after 1 mg dexamethasone) 12.3 μg/dL (339 nmol/L) (high) <1.8 μg/dL (<50 nmol/L) adequate suppression
Dexamethasone level(after 1 mg dexamethasone) 336 ng/dL (8.64 nmol/L) (normal) >200 ng/dL (>5.2 nmol/L) adequate absorption
ACTH level (after 1 mg dexamethasone) 242 pg/mL (53.27 pmol/L) (not suppressed) 10–60 pg/mL (2.2–13.2 pmol/L)
Abbreviations: μg/d = micrograms per day; μg/dL = Micrograms per deciliter; μg/L = micrograms per liter; μmol/L = micromoles per liter; AM = morning (Ante Meridiem); nmol/L = nanomoles per Liter; ng/mL/h = nanograms per milliliter per hour; pmol/L = picomoles per liter; pg/mL = picograms per milliliter; μg/L/h = micrograms per liter per hour; ng/dL = nanograms per deciliter; nmol/d = nanomoles per day.
Inferior petrosal sinus sampling (IPSS) was performed using contrast-enhanced fluoroscopy to confirm accurate catheter placement in both inferior petrosal sinuses. Absolute ACTH values obtained during IPSS are shown in (Table 2). The central-to-peripheral ACTH gradient at baseline was 1.1, which is below the diagnostic threshold of 2.0 typically required to support a pituitary source of ACTH. Following desmopressin acetate (DDAVP) stimulation, peak left: peripheral and right: peripheral ACTH ratios reached 1.7 and 1.5, respectively—well below the accepted post-stimulation cut-off of 3.0. In addition, the left: right petrosal ACTH ratios remained between 1.03 and 1.15 throughout the sampling period, indicating no significant lateralization of ACTH secretion. These findings are not consistent with Cushing’s disease and instead support a diagnosis of ectopic ACTH syndrome.

Table 2. Bilateral Petrosal Sinus and Peripheral Adrenocorticotropin Levels Before and After Intravenous Injection of Desmopressin Acetate (DDAVP) 10 mcg

Time post DDAVP, min Left petrosal ACTH Left: peripheral ACTH Right petrosal ACTH Right: peripheral ACTH Peripheral ACTH Left: right petrosal ACTH
0 165 pg/mL (36.3 pmol/L) 1.1 160 pg/mL (35.2 pmol/L) 1.1 150 pg/mL (33.0 pmol/L) 1.03
3 270 pg/mL (59.4 pmol/L) 1.6 245 pg/mL (53.9 pmol/L) 1.4 170 pg/mL (37.4 pmol/L) 1.10
5 320 pg/mL (70.4 pmol/L) 1.7 285 pg/mL (62.7 pmol/L) 1.5 185 pg/mL (40.7 pmol/L) 1.12
10 350 pg/mL (77.0 pmol/L) 1.4 305 pg/mL (67.2 pmol/L) 1.2 250 pg/mL (55.0 pmol/L) 1.15
Abbreviations: ACTH = adrenocorticotropin; DDAVP = desmopressin acetate; pg/mL = picograms per milliliter; pmol/L = picomoles per liter.
Magnetic resonance imaging of the head could not be performed due to a history of retained shrapnel in the neck from combat in Vietnam. Noncontrast computed tomography (CT) images of the head and paranasal sinuses revealed no evidence of a pituitary tumor but demonstrated an expansile mass measuring approximately 2.4 × 4.3 × 3.3 cm, centered within the bilateral ethmoid sinuses with extension into both the anterior and posterior ethmoidal air cells (Fig. 1A, B). A contrast-enhanced CT scan of the abdomen, performed following improvement in renal function, demonstrated marked bilateral adrenal gland enlargement (Fig. 1C).

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Fig. 1. (A) Axial and (B) coronal noncontrast computed tomography (CT) images of the head demonstrate a heterogeneous soft tissue mass at the anterior skull base extending toward the cribriform plate and into the right nasal cavity, involving the ethmoid sinus and eroding the lamina papyracea, resulting in medial displacement of the right orbital contents (blue arrows). (C) Axial contrast-enhanced CT of the abdomen reveals bilateral adrenal gland enlargement. (D) Whole-body single-photon emission computed tomography/computed tomography (SPECT/CT) using indium-111 pentetreotide demonstrates intense radiotracer uptake localized to the biopsy-confirmed esthesioneuroblastoma in the ethmoid sinuses, with no evidence of metastatic octreotide-avid lesions. (G) Coronal contrast-enhanced CT scan of the abdomen, performed after surgery, shows normalization in the size of both adrenal glands. (E) Coronal and (F) axial noncontrast CT images of the paranasal sinuses obtained postoperatively demonstrate complete surgical resection of the tumor.

The otolaryngology (ENT) team was consulted and recommended an endoscopic biopsy of the nasal mass. Histopathologic examination revealed a Hyams Grade 2 olfactory neuroblastoma (Fig. 2A, B), characterized by well-circumscribed lobules of small round blue cells with scant cytoplasm, a neurofibrillary background matrix, and low mitotic activity, without necrosis or rosette formation—findings typical of a moderately differentiated tumor in the Hyams grading system.

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Fig. 2. (A) Low-power H&E (4×) shows well-circumscribed lobules of small round blue cells with fibrovascular stroma and a neurofibrillary matrix; no necrosis or rosettes are seen. (B) High-power H&E (40×) reveals neoplastic cells with high nuclear-to-cytoplasmic ratio, hyperchromatic nuclei, and granular chromatin, consistent with Hyams Grade 2 ONB. (C) Chromogranin A shows granular cytoplasmic positivity in tumor nests, confirming neuroendocrine differentiation. (D) Synaptophysin shows diffuse granular cytoplasmic staining in tumor clusters, with negative stromal background. (E) S-100 highlights sustentacular cells in a peripheral pattern around tumor nests. (F) ACTH staining shows patchy to diffuse cytoplasmic positivity in tumor cells, confirming ectopic ACTH production in ONB. A nuclear medicine octreotide scan (111 Indium-pentetreotide scintigraphy) with single-photon emission computed tomography/computed tomography (SPECT/CT) demonstrated intense radiotracer uptake in the biopsy-proven esthesioneuroblastoma centered within the ethmoid sinuses, confirming the tumor’s expression of somatostatin receptors. There was no evidence of locoregional or distant metastatic disease demonstrating octreotide avidity (Fig. 1D).

Immunohistochemical staining supported the diagnosis: tumor cells were positive for chromogranin A (Fig. 2C), synaptophysin (Fig. 2D), and S-100 (Fig. 2E). Chromogranin A and synaptophysin are markers of neuroendocrine differentiation, confirming the tumor’s neuroendocrine origin. S-100 positivity in the sustentacular cells surrounding tumor nests is a classic feature of olfactory neuroblastoma. Staining was negative for neurofilament protein, AE1/AE3, and epithelial membrane antigen, helping exclude other small round blue cell tumors, such as neuroendocrine carcinoma or sinonasal undifferentiated carcinoma. Importantly, the tumor cells showed positive cytoplasmic staining for ACTH (Fig. 2F), confirming ectopic ACTH production by the tumor itself. This finding definitively links the olfactory neuroblastoma as the source of paraneoplastic ACTH secretion, consistent with the patient’s clinical picture of ectopic Cushing’s syndrome.

Treatment

Hypokalemia was corrected, and oral ketoconazole 200 mg twice daily was initiated preoperatively to mitigate the metabolic complications of hypercortisolism. Ketoconazole was discontinued on the day of surgery. The tumor was resected via an endoscopic endonasal approach. A blood sample was obtained immediately following tumor removal for measurement of ACTH and cortisol levels. Intravenous hydrocortisone (100 mg every 6 h) was initiated promptly thereafter. Postoperative cortisol and ACTH levels were undetectable: cortisol <5 μg/dL [<138 nmol/L] (normal: 5–25 μg/dL [138–690 nmol/L]); ACTH <5 pg/mL [<1.1 pmol/L] (normal: 10–60 pg/mL [2.2–13.3 pmol/L]). These findings confirmed successful surgical resection of the ACTH-secreting tumor. These issues extended the hospital stay and required treatment with antiseizure medications, antibiotics, and additional surgeries by ENT and Neurosurgery teams.

Outcome and Follow-Up

The patient demonstrated significant normalization of blood pressure (124/78 mmHg), fasting blood glucose (95 mg/dL [5.3 mmol/L]), and potassium (4.3 mEq/L [4.3 mmol/L]) within 2 weeks postoperatively. ACTH levels decreased from preoperative values of 220–250 pg/mL (48.4–55.2 pmol/L) to 29 pg/mL (5.5 pmol/L), and morning (AM) cortisol levels decreased from preoperative values of 29 μg/dL (800 nmol/L) to 12 μg/dL (331 nmol/L). These values were obtained at 2 weeks postoperatively. While early normalization of ACTH and cortisol levels could raise concern for residual disease, the patient’s subsequent sustained biochemical remission, clinical recovery, and a robust response to cosyntropin stimulation at 3 months post-op were reassuring. Adjuvant radiotherapy was also administered to mitigate any potential risk of recurrence.
He was subsequently transferred to an inpatient rehabilitation facility while receiving oral hydrocortisone replacement therapy, during which his functional status progressively improved. The patient was later discharged home on oral hydrocortisone replacement therapy with plans for continued outpatient physical therapy. Hydrocortisone was gradually tapered and discontinued 3 months after surgery, at which point blood pressure (122/76 mmHg), fasting glucose (90 mg/dL [5.0 mmol/L]), potassium (4.2 mEq/L [4.2 mmol/L]), ACTH (25 pg/mL [4.9 pmol/L]), and AM cortisol (15 μg/dL [414 nmol/L]) demonstrated sustained normalization. Following administration of 250 mcg intramuscular cosyntropin, serum cortisol peaked at 21 μg/dL (580 nmol/L), confirming an adequate adrenal reserve and complete recovery of the hypothalamic–pituitary–adrenal axis. Additionally, late-night salivary cortisol was remeasured on 2 occasions after hydrocortisone discontinuation and found to be 0.04 μg/dL (1.10 nmol/L) and 0.03 μg/dL (0.83 nmol/L), both within normal reference limits (≤0.09 μg/dL [≤2.5 nmol/L]). A 24-hour UFC collected at the same time measured 38 μg/d (105 nmol/d), confirming biochemical resolution of hypercortisolism. Cushing’s stigmata, including muscle weakness and skin changes, showed marked improvement by 3 months postoperatively (Table 3).

Table 3. Timeline of Clinical and Biochemical Recovery Following Resection of Ectopic ACTH-Secreting Olfactory Neuroblastoma

Parameter Preoperative value 24–48 h Postop 2 wks postop 3 mo postop Normal range
Blood pressure 171/84 mmHg 140/80 mmHg 124/78 mmHg 122/76 mmHg <130/80 mmHg
Fasting glucose 244 mg/dL (13.5 mmol/L) 160 mg/dL (8.9 mmol/L) 95 mg/dL (5.3 mmol/L) 90 mg/dL (5.0 mmol/L) 70–99 mg/dL (3.9–5.5 mmol/L)
Potassium 1.6 mEq/L (1.6 mmol/L) 3.8 mEq/L (3.8 mmol/L) 4.3 mEq/L (4.3 mmol/L) 4.2 mEq/L (4.2 mmol/L) 3.5–5.0 mEq/L (3.5–5.0 mmol/L)
ACTH 220–250 pg/mL (48.4–55.2 pmol/L) <10 pg/mL (<2.2 pmol/L) 29 pg/mL (5.5 pmol/L) 25 pg/mL (4.9 pmol/L) 10–60 pg/mL (2.2–13.3 pmol/L)
AM cortisol 29 μg/dL (800 nmol/L) <5 μg/dL (<138 nmol/L) 12 μg/dL (331 nmol/L) 15 μg/dL (414 nmol/L); Cosyntropin peak: 21 μg/dL (580 nmol/L) 5–25 μg/dL (138–690 nmol/L); adequate response >18 μg/dL (500–550 nmol/L)
LNSC 0.27/0.36 μg/dL (7.45/9.93 nmol/L) — — 0.04/0.03 μg/dL (1.10/0.83 nmol/L) ≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
UFC (24-h) 5880/4920 μg/d (16 223/13 576 nmol/d) — — 38 μg/d (105 nmol/d) ≤60 μg/d (≤165 nmol/d)
Cushing’s Stigmata Moon facies, dorsocervical fat pad, violaceous striae, severe muscle weakness No change Partial improvement: BP/glucose control; decreased edema Marked improvement; muscle strength restored; striae fading Not applicable
Abbreviations: ACTH = adrenocorticotropin; mmHg = illimeters of mercury; mEq/L = milliequivalents per liter; mg/dL = milligrams per deciliter; mmol/L = millimoles per liter; μg/dL = micrograms per deciliter; AM = morning (Ante Meridiem); pg/mL = picograms per milliliter; pmol/L = picomoles per liter; nmol/L = nanomoles per liter.
dfA follow-up CT scan of the adrenals with contrast, performed following improvement in renal function, confirmed normalization in the size of the previously enlarged adrenal glands (Fig. 1E). A follow-up CT of sinuses without contrast confirmed complete resection of the tumor (Fig. 1F, G).
Adjuvant radiotherapy was recommended in view of the patient’s Kadish stage B tumor, Hyams grade 2 histology, and the elevated risk of local recurrence inherent to olfactory neuroblastoma. Despite complete surgical excision, radiotherapy was pursued to mitigate recurrence risk, particularly considering the tumor’s ectopic ACTH secretion, which suggested biologically aggressive behavior, as well as the patient’s satisfactory functional status and anticipated favorable treatment tolerance. A total of 30 fractions of 2 Gy were administered using volumetric modulated arc therapy.

Discussion

Diagnostic Considerations

EAS poses a significant diagnostic challenge due to its variable presentation and the urgency of identifying the source of ACTH excess. ONB, although rare, should be considered in patients with ACTH-dependent Cushing syndrome who present with sinonasal masses. ONB accounts for only 2% to 3% of all malignant sinonasal tumors,4,6 with fewer than 25 cases documented as sources of ectopic ACTH production.3,11,12
While ectopic ACTH syndrome remains the most well-recognized endocrine manifestation of ONB, a broader spectrum of paraneoplastic syndromes has also been described. These include syndrome of inappropriate antidiuretic hormone secretion, paraneoplastic hypercalcemia—often mediated by parathyroid hormone–related protein—and catecholamine excess mimicking pheochromocytoma.11 These atypical presentations underscore the neuroendocrine complexity of ONB and the diagnostic challenges they pose.
Diagnosis involves biochemical confirmation of hypercortisolism using low-dose dexamethasone suppression, 24-hour UFC, late-night salivary cortisol, and plasma ACTH levels. Interestingly, despite markedly elevated ACTH levels, our patient exhibited a low DHEA-S concentration and a normal aldosterone level. This biochemical pattern supports previous observations that EAS may present with a dissociation in adrenal steroidogenesis. Chronic hypercortisolemia may suppress the zona reticularis,13 while ectopic ACTH-producing tumors may secrete aberrant precursors that preferentially stimulate glucocorticoid rather than androgen synthesis.14 Cortisol excess can also downregulate key enzymes such as 17,20-lyase and SULT2A1, thereby impairing DHEA-S production.15 Moreover, the rapid onset and severity of ectopic ACTH production may preclude the compensatory DHEA-S rise typically observed in pituitary-driven Cushing disease. Although cortisol excess is known to suppress the renin-angiotensin-aldosterone system, aldosterone levels may remain detectable in certain EAS cases, particularly in early-stage or physiologically variable presentations.16
Once ACTH-dependence is established, localization of the tumor becomes essential. IPSS, although considered the gold standard for distinguishing pituitary from ectopic ACTH sources, may yield inconclusive results in cases of ONB due to altered venous drainage pathways.3 Functional imaging with 111In-octreotide single-photon emission computed tomography/computed tomography or 68Ga-DOTATATE positron emission tomography/computed tomography facilitates localization of neuroendocrine tumors that express somatostatin receptors. Histopathologic confirmation using ACTH immunostaining and neuroendocrine markers such as chromogranin A, synaptophysin, and S-100 is essential to confirm diagnosis.

Therapeutic Approach and Challenges

Surgical resection remains the cornerstone of management for ACTH-producing ONB.9 Endoscopic endonasal approaches are preferred when anatomically feasible due to their minimally invasive nature and favorable access to the anterior skull base. Preoperative pharmacologic inhibition of cortisol biosynthesis (utilizing ketoconazole, which was specifically selected for our patient, metyrapone, or etomidate) represents a critical intervention to attenuate hypercortisolism-related metabolic complications and minimize perioperative morbidity.3,8 Intraoperative glucocorticoid replacement should be administered following tumor resection to prevent adrenal insufficiency. Postoperative complications—such as cerebrospinal fluid leak or infection—require prompt multidisciplinary intervention.
Adjuvant radiotherapy is generally recommended for intermediate-to high-grade ONBs, even after gross total resection, given their aggressive behavior and high risk of recurrence. Volumetric modulated arc therapy delivers precise radiation doses while minimizing toxicity to adjacent structures.5,9 Platinum-based chemotherapy remains a therapeutic option in patients with unresectable or metastatic disease.9
Emerging therapeutic strategies include somatostatin receptor–directed theranostics. Zhi et al (2025) recently demonstrated the dual diagnostic and therapeutic potential of 68Ga-DOTATATE positron emission tomography/computed tomography imaging and 177Lu-DOTATATE peptide receptor radionuclide therapy in ONB, offering promising future directions for patients with advanced or somatostatin receptor–positive disease.17

Prognosis and Future Directions

The prognosis of ONB is influenced by Kadish staging, Hyams histologic grading, and treatment strategy. Recurrence rates are reported to range from 30% to 60%,9,18 and 5-year survival rates vary from 45% to 80% depending on tumor grade, stage, and completeness of resection.6,19 Early detection, complete surgical resection, and multimodal therapy, including radiotherapy, are associated with improved outcomes. Lifelong follow-up with serial imaging and endocrine evaluation is essential to monitor for recurrence and late-onset adrenal insufficiency.10,19
Continued advancements in molecular imaging and targeted therapies, particularly those leveraging somatostatin receptor biology, may expand the therapeutic landscape for patients with recurrent or progressive ONB.

Conclusion

This case highlights the importance of timely diagnosis, comprehensive biochemical and radiologic assessment, and coordinated multidisciplinary management in ACTH-producing ONB. In addition to surgery and preoperative endocrine stabilization, adjuvant radiotherapy and long-term surveillance are critical components of care. As somatostatin receptor–based imaging and theranostic therapies evolve, they offer exciting opportunities to individualize treatment in this rare but challenging neuroendocrine malignancy.

Statement of Patient Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Disclosure

The author has no conflict of interest to disclose.

References

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