Bone Material Strength Index Is Low in Patients With Cushing’s Syndrome Even After Long-term Remission

Posted on December 18, 2025 by MaryO

I sure know this to be true, even though my surgery was in 1987

Abstract

Objective

Hypercortisolism in endogenous Cushing’s syndrome (CS) results in decreased bone mineral density (BMD) and increased fracture risk. Although after remission BMD improves, the fracture rate remains elevated, suggesting that BMD may not adequately reflect fracture risk in this group. The aim was to evaluate bone material properties, another component of bone quality, using impact microindentation in patients with CS in remission.

Methods

Cross-sectional study in 60 CS patients and 60 age-, sex-, and BMD-matched controls at a tertiary referral center between 2019 and 2021. Bone material strength index (BMSi) was measured by impact microindentation using the OsteoProbe® device at the tibia. In addition, laboratory investigation, BMD, and vertebral fracture assessment were performed.

Results

By design, patients and controls were comparable for age (median age 56.5 years), sex (48 women), and BMD at the lumbar spine and femoral neck. They were also comparable regarding the number of fragility fractures (21 vs 27, P = .22). The median time of remission in patients was 6 years (range 1 to 41). Despite comparable BMD, BMSi was significantly lower in CS patients compared to controls (76.2 ± 6.7 vs 80.5 ± 4.9, P < .001). In CS patients, BMSi was negatively correlated with body mass index (r = −0.354, P = .01) but not related to the presence of fracture, physiological hydrocortisone replacement use, other pituitary insufficiencies, or time since remission.

Conclusion

Bone material properties remain altered in patients with endogenous CS, even after long-term remission. These abnormalities, known to be associated with fractures in other populations, may play a role in the persistent bone fragility of steroid excess.

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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

  1. Castinetti F, Brue T: Impact of Cushing’s syndrome on fertility and pregnancy. Ann Endocrinol (Paris). 2022, 83:188-90. 10.1016/j.ando.2022.04.001
  2. Eschler DC, Kogekar N, Pessah-Pollack R: Management of adrenal tumors in pregnancy. Endocrinol Metab Clin North Am. 2015, 44:381-97. 10.1016/j.ecl.2015.02.006
  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
  6. Martínez García R, Martínez Pérez A, Domingo del Pozo C, Sospedra Ferrer R: Cushing’s syndrome in pregnancy. Laparoscopic adrenalectomy during pregnancy: the mainstay treatment. J Endocrinol Invest. 2016, 39:273-6. 10.1007/s40618-015-0345-0
  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
  9. Jung C, Ho JT, Torpy DJ, et al.: A longitudinal study of plasma and urinary cortisol in pregnancy and postpartum. J Clin Endocrinol Metab. 2011, 96:1533-40. 10.1210/jc.2010-2395
  10. Petraglia F, Sawchenko PE, Rivier J, Vale W: Evidence for local stimulation of ACTH secretion by corticotropin-releasing factor in human placenta. Nature. 1987, 328:717-19. 10.1038/328717a0
  11. Savas M, Mehta S, Agrawal N, van Rossum EF, Feelders RA: Approach to the patient: diagnosis of Cushing syndrome. J Clin Endocrinol Metab. 2022, 107:3162-74. 10.1210/clinem/dgac492
  12. Jung E, Romero R, Yeo L, et al.: The etiology of preeclampsia. Am J Obstet Gynecol. 2022, 226:S844-66. 10.1016/j.ajog.2021.11.1356
  13. González P, Lozano P, Ros G, Solano F: Hyperglycemia and oxidative stress: an integral, updated and critical overview of their metabolic interconnections. Int J Mol Sci. 2023, 24:9352. 10.3390/ijms24119352
  14. Ueda A, Hasegawa M, Matsumura N, et al.: Lower systolic blood pressure levels in early pregnancy are associated with a decreased risk of early-onset superimposed preeclampsia in women with chronic hypertension: a multicenter retrospective study. Hypertens Res. 2022, 45:135-45. 10.1038/s41440-021-00763-6
  15. Burton GJ, Jauniaux E: Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol. 2018, 218:S745-61. 10.1016/j.ajog.2017.11.577
  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
  20. Nigri G, Rosman AS, Petrucciani N, et al.: Meta-analysis of trials comparing laparoscopic transperitoneal and retroperitoneal adrenalectomy. Surgery. 2013, 153:111-19. 10.1016/j.surg.2012.05.042

From https://www.cureus.com/articles/425273-adrenal-cushings-syndrome-in-pregnancy-complicated-by-fetal-growth-restriction-following-retroperitoneoscopic-adrenalectomy#!/

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Identification of Endogenous Hypercortisolism and the Effect of Mifepristone Treatment in Patients With Difficult-to-Manage Diabetes: A Case Series

Posted on December 3, 2025 by MaryO
Endogenous hypercortisolism (Cushing syndrome) is a multisystemic disease characterized by a wide range of clinical signs and symptoms. Its heterogeneous presentation can cause significant diagnostic delays, and prolonged exposure to excess cortisol activity can contribute to cardiometabolic abnormalities such as diabetes. When diabetes remains unresponsive or only partially responsive to standard-of-care treatment, clinicians should consider hypercortisolism as a potential underlying driver.Despite the risks associated with hypercortisolism, guidance on identifying and managing it in patients with diabetes remains limited. This article presents a case series of 10 patients from a single practice who were screened for hypercortisolism because of difficult-to-manage diabetes and additional comorbidities. All patients were treated for hypercortisolism with mifepristone, resulting in significant clinical improvements including weight loss, improved glycemic control, and reduced medication needs.

This real-world case series highlights the importance of recognizing hypercortisolism as a differential diagnosis and a potential contributing factor to difficult-to-manage diabetes despite standard-of-care therapies. Addressing hypercortisolism with mifepristone can result in substantial clinical benefits.

This article contains supplementary material online at https://doi.org/10.2337/figshare.30351361.

PDF of article here.

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Using the Desmopressin Stimulation Test to Assess for Residual Tumor in Cushing Disease With Cyclic Hypercortisolism

Posted on October 26, 2025 by MaryO

Abstract

Cushing disease is caused by excess ACTH secretion by a pituitary adenoma leading to hypercortisolism. Cyclic Cushing syndrome, in which periods of cortisol excess are interspersed by periods of normal or low values, poses a challenge to diagnostic testing and postoperative monitoring. We present a 26-year-old woman with cyclic Cushing syndrome who achieved apparent biochemical remission after transsphenoidal resection of an ACTH-producing pituitary tumor, confirmed on pathology. Despite initial clinical improvement, she later experienced recurring symptoms. Biochemical evidence of hypercortisolism was documented, but 1 month later morning serum cortisol was undetectable. A desmopressin stimulation test (DesST) produced a rise in ACTH and cortisol, indicating likely residual tumor tissue. After repeat surgery, pathology again confirmed an ACTH-secreting tumor. Postoperatively, ACTH and cortisol levels were again low, but a repeat DesST was now negative, suggesting successful resection of the residual tumor, and she remains in remission 3 years later. This case describes the unique utility of the DesST to detect a pituitary corticotroph tumor in cyclic Cushing disease during periods of low disease activity. It also highlights the potential role of the DesST in postoperative monitoring.

Cushing disease, cyclic Cushing, desmopressin stimulation test
Issue Section:

Case Report

Introduction

Cushing disease (CD), in which excess ACTH from a pituitary adenoma drives hypercortisolism, causes up to 70% of endogenous Cushing syndrome (CS) [1]. When possible, the first-line treatment for CD is transsphenoidal surgery (TSS) to remove the causative tumor. This leads to remission in approximately 80% of cases, with recurrence rates estimated at 20% [2].

Cyclic CS, in which periods of excess cortisol are interspersed with periods of normal or low cortisol, complicates both the initial diagnosis of CS and the interpretation of post-TSS hormone levels [3]. Basal ACTH and cortisol, and dexamethasone suppression tests performed during a period of low disease activity, can be misleading because they reflect healthy pituitary corticotrophs that are responsive to and suppressed by persistent hypercortisolism [4]. The same mechanism of corticotroph suppression pertains after TSS, so that very low morning plasma ACTH and serum cortisol levels (generally less than 10 pg/mL [SI: 2.2 pmol/L] and 5 µg/dL [SI: 138 nmol/L], respectively), indicate successful tumor resection [5, 6]. However, if postoperative testing occurs during a period of low disease activity in cyclic CS, it may falsely indicate remission.

The desmopressin stimulation test (DesST), in which ACTH and cortisol levels are measured following intravenous administration of 10 µg desmopressin, may help to resolve these problems. Most corticotroph adenomas respond to desmopressin with an increase in ACTH secretion, followed by a cortisol increase [7, 8]. By contrast, most healthy people do not respond. Desmopressin, a synthetic analogue of arginine vasopressin (AVP), is believed to trigger this response by binding to upregulated V3 receptors or ectopically expressed V2 receptors on corticotroph adenomas [9]. Some of the most commonly used response criteria for the DesST, ≥35% and ≥20% increases in ACTH and cortisol, respectively, are based on thresholds that produce high performance for the CRH stimulation test [10]. Currently, however, there is no clear consensus on optimal cutoffs for the DesST [9].

The return of a positive DesST response has been shown to precede the return of hypercortisolism when monitoring for recurrence of CD [11]. By analogy, we postulated that a postoperative DesST might identify residual tumor in a patient with cyclic CS. In this case presentation, we will highlight the utility of the DesST to establish both partial and successful tumor resection in such a patient.

Case Presentation

A 26-year-old woman developed irregular menses, hair loss, facial rounding, a dorsocervical fat pad, and wide violaceous abdominal striae, accompanied by an unexplained 30-pound weight gain over 3 months. Over the same period, she also noted worsening of longstanding fatigue, anxiety, depression, and acne. Eventually, 1 year after these symptoms started, she was diagnosed with CS based on elevated midnight serum cortisol (24.5 µg/dL [SI: 675 nmol/L], reference range [RR]: <7.5 µg/dL [<207 nmol/L]), 24-hour urine free cortisol (UFC) (337 µg/day [SI: 931 nmol/day], RR: 3.5-45 µg/day [SI: 9.7-124 nmol/day]), and failure to suppress serum cortisol during a 48-hour low-dose dexamethasone suppression test (48-hour cortisol: 26.7 µg/dL [SI: 736 nmol/L], RR: <1.8 µg/dL [SI: <50 nmol/L]). ACTH was not suppressed and pituitary magnetic resonance imaging (MRI) revealed a right-sided 7 mm microadenoma. Bilateral inferior petrosal sinus sampling showed a high central-to-peripheral ACTH ratio, indicative of CD.

Because of surgical delays related to the COVID-19 pandemic, she was started on a block-and-replace regimen of metyrapone and hydrocortisone (HC) before undergoing TSS 6 months later, removing a tumor located in the right superior posterior portion of the pituitary. Pathology confirmed a pituitary tumor with diffuse positivity for ACTH, rare positivity for GH and prolactin, and low mitotic activity (Ki67 index <3%). Morning serum cortisol dropped to 1.2 µg/dL (SI: 33 nmol/L) (RR: 3.7-19.4 µg/dL [SI: 102-535 nmol/L]) on postoperative day 4, at which point physiologic HC replacement was started. HC was eventually tapered and stopped 8 months later, when morning serum cortisol had recovered. Postoperatively, her acne and menstrual irregularities resolved while hair loss continued and her weight stabilized without any significant reduction.

Later, she again developed worsening anxiety and a severely depressed mood to the point where she could barely function at her job. Because of these worsening symptoms, repeat testing was performed 10 months after surgery, confirming return of hypercortisolism: midnight serum cortisol 20.5 µg/dL (SI: 565 nmol/L), UFC 82 µg/day (SI: 227 nmol/day). A small lesion was seen on pituitary MRI, thought to represent postoperative changes or a residual adenoma.

Diagnostic Assessment

The patient presented to our institution for a second opinion. A pituitary MRI was unchanged from the month prior. Unexpectedly, laboratory values now showed undetectable bedtime salivary (<50 ng/dL [SI: 1.4 nmol/L], RR: <100 ng/dL [SI: <2.8 nmol/L]) and morning serum cortisol (<1 µg/dL [SI: <27.6 nmol/L]), and low-normal ACTH (11.9 pg/mL [SI: 2.6 pmol/L], RR: 5.0-46.0 pg/mL [SI: 1.1-10.1 pmol/L]), and UFC (5.6 µg/day [SI: 15.5 nmol/day]). She did not have clinical symptoms of adrenal insufficiency. These results, indicative of secondary adrenal insufficiency, were in stark contrast to the hypercortisolism confirmed 1 month earlier, raising suspicion for apoplexy of residual tumor tissue or cyclic CS. Upon further questioning, the patient reported previous waxing and waning of acne severity, but no clear cyclicity of other symptoms. She felt that it was not possible for her to assess emotional or cognitive variability apart from that caused by the COVID-19 pandemic. Three weeks later, she underwent a DesST, during which baseline cortisol and ACTH were 3.1 µg/dL (SI: 86 nmol/L) and 34.1 pg/mL (SI: 7.5 pmol/L), respectively. After desmopressin, ACTH increased +111% at +15/30 minutes and cortisol increased +172% at +30/45 minutes (Fig. 1). This positive response was interpreted as confirming the presence of residual tumor tissue.

ACTH and cortisol responses during the desmopressin stimulation test (DesST) before and after the patient's second transsphenoidal surgery. Plasma ACTH (A) and serum cortisol (B) levels were measured twice at baseline before and 15, 30, 45, and 60 minutes after intravenous administration of 10 µg desmopressin. Circles and squares represent the values from tests performed before and after surgery, respectively. The presence of a response (despite a low baseline cortisol level) in the preoperative test was considered to represent residual corticotroph tumor tissue; the postoperative loss of response to desmopressin was thought to represent successful resection of residual tumor.

Figure 1.

ACTH and cortisol responses during the desmopressin stimulation test (DesST) before and after the patient’s second transsphenoidal surgery. Plasma ACTH (A) and serum cortisol (B) levels were measured twice at baseline before and 15, 30, 45, and 60 minutes after intravenous administration of 10 µg desmopressin. Circles and squares represent the values from tests performed before and after surgery, respectively. The presence of a response (despite a low baseline cortisol level) in the preoperative test was considered to represent residual corticotroph tumor tissue; the postoperative loss of response to desmopressin was thought to represent successful resection of residual tumor.

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Treatment

Two weeks after the positive DesST, on admission for repeat TSS, morning serum cortisol had risen to 15.2 µg/dL (SI: 419 nmol/L). After resection of residual tissue within the anteroinferior and right lateral aspect of the gland, pathology again confirmed a focus of ACTH-positive tumor. By postoperative day 3, morning serum cortisol was again undetectable with an unchanged plasma ACTH of 12.1 pg/mL (SI: 2.7 pmol/L). Because of the difficulty in distinguishing a satisfactory postoperative biochemical response from a period of low disease activity in cyclic CS, a second DesST was performed. This time the test was negative, with ACTH increasing by only 8%, whereas cortisol remained undetectable throughout (Fig. 1). This drastic change in response to desmopressin was believed to represent successful resection of residual tumor tissue. She was discharged on physiologic HC replacement and daily desmopressin after developing postoperative AVP deficiency.

Outcome and Follow-up

The AVP deficiency resolved over 6 months, whereas HC was stopped after 8 months, following a normal insulin tolerance test. The patient lost 20 pounds in the first 9 months after her second surgery, before gradually losing an additional 40 pounds over the following 3 years, reaching her baseline weight. The facial rounding and dorsocervical fat pad resolved, and acne improved. Three years after her second surgery, biochemical remission was maintained but she continued to experience hair loss, reduced taste and smell, and fluctuating severity of her preexisting fatigue, anxiety, and depression.

Discussion

Of note, our patient’s initial evaluation and surgery took place at an expert pituitary center in the United Kingdom, whereas the second evaluation was performed in the United States. This case shows some regional differences in testing protocols; for example, the 48-hour dexamethasone suppression and insulin tolerance tests are used more often in the United Kingdom. However, both surgical procedures were performed by high-volume pituitary surgeons, which is crucial to maximize the probability of remission [2].

While previous reports have described the role of the DesST in CD diagnosis [9], our case highlights its unique utility during periods of low disease activity in cyclic CD. Other tests for the diagnosis or etiology of CS rely on ongoing disease activity and require ongoing tumoral secretion of ACTH accompanied by suppression of healthy corticotrophs. Importantly, most healthy corticotrophs do not exhibit a significant response to desmopressin [7, 9]. In our patient, the diagnosis of CD was confirmed based on previous surgical pathology. Although documented recurrent hypercortisolism and CS symptoms were highly suspicious, the presence of residual disease was questioned due to the lack of ongoing hypercortisolism. In this context, the clearly positive response to DesST provided supportive evidence for pursuing a second TSS. The subsequent postoperative loss of response to desmopressin was interpreted as representing successful resection of all residual tumor tissue, which was supported by enduring remission of most symptoms 3 years after surgery. Biochemical postoperative assessments are based on trends in ACTH and cortisol. Typically, both hormones plummet after successful removal of an ACTH-producing tumor, since healthy corticotrophs remain suppressed because of longstanding hypercortisolism. Corticotrophs take at least 6 months to recover; earlier normalization of ACTH and cortisol raises concern for residual tumor tissue [12].

Postoperative hormonal trends may be different in 2 settings that were both relevant to our patient: preoperative medical therapy to restore eucortisolism and cyclic CS. In both scenarios, recent hypercortisolism may have been mild or absent, potentially allowing for a swift recovery of healthy corticotrophs. Postoperative ACTH and cortisol levels may be normal, making it difficult to establish a biochemical cure. In this setting, the usual screening tests for hypercortisolism (UFC, bedtime cortisol, low-dose dexamethasone suppression test) are useful to determine whether excessive ACTH secretion persists.

However, these postoperative screening tests for hypercortisolism may not be reliable in cyclic CS since low or normal ACTH and cortisol levels can reflect either remission or low disease activity. The DesST may be particularly useful in this situation to identify residual disease or confirm successful tumor resection. For this test to be useful, however, it is important to obtain a preoperative DesST to establish a baseline because a minority of tumors causing CD do not respond to desmopressin [9].

Learning Points

  • Most healthy pituitary corticotrophs and tumors causing ectopic ACTH syndrome do not exhibit a response during the desmopressin stimulation test (DesST), making it useful for Cushing disease (CD) diagnosis.

  • The DesST may be particularly useful during periods of low disease activity in cyclic Cushing syndrome, as other dynamic tests used to diagnose CD may be uninterpretable in this setting.

  • Postoperatively, the DesST may be useful to confirm successful tumor resection and to monitor for CD recurrence. It is, however, important to obtain a preoperative DesST to establish whether the causative tumor is responsive to desmopressin.

Contributors

All authors made individual contributions to authorship. B.M.B., L.K.N., and H.E. were involved in the writing and submission of the manuscript. W.D., R.M., L.K.N., and H.E. were involved in the diagnosis and management of this patient. All authors reviewed and approved the final draft.

Funding

This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH). The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

Disclosures

B.M.B., W.D., R.M., and H.E. have nothing to disclose. L.K.N. receives royalties from UpToDate.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Published by Oxford University Press on behalf of the Endocrine Society 2025.
This work is written by (a) US Government employee(s) and is in the public domain in the US. See the journal About page for additional terms.

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

Osilodrostat for Cyclic Cushing’s Disease

Posted on October 24, 2025 by MaryO

Highlights

  • •
    Cyclic Cushing’s syndrome (CCS) is a rare entity with significant comorbidities
  • •
    It is defined by at least 3 peaks of hypercortisolism, 2 troughs of eucortisolism
  • •
    Surgical cure is preferred, and medications are second-line
  • •
    Our case is the first showing successful treatment of native CCS with osilodrostat
  • •
    Osilodrostat showed rapid onset/offset and reversible inhibition of steroidogenesis

Abstract

Background/Objective

Cyclic Cushing’s syndrome is a rare subtype of Cushing’s syndrome with episodes of hypercortisolism, followed by spontaneous remission.

Case Report

Our patient was a 68-year-old male who presented with his third cycle of cyclic Cushing’s disease with facial swelling, buffalo hump, fatigue, proximal muscle weakness, and lower extremity edema. Laboratory tests showed the following: 24-hour urine free cortisol 12030.3 mcg/d (normal <= 60.0 mcg/d), morning adrenocorticotropic hormone (ACTH) 464 pg/mL (normal 6-59 pg/mL), morning serum cortisol 91 mcg/dL (normal 8-25 mcg/dL), and potassium 3.3 mmol/L (normal 3.6-5.3 mmol/L). MRI pituitary without/with contrast showed a partially empty sella. Prior inferior petrosal sinus sampling during the second cycle indicated a potential pituitary source of increased ACTH production, localized or draining to the right side. The patient was treated with osilodrostat with improvement in laboratory values and clinical symptoms by 2-3 weeks. After development of adrenal insufficiency (AI), osilodrostat was rapidly titrated off by 2 months of treatment. Subsequently, labs after 8 days off osilodrostat confirmed clinical remission and reversibility of medication-induced AI.

Discussion

Since hypercortisolism is associated with mortality risk and comorbidities, timely management is a priority. If a surgical cure is not possible, a medication that treats hypercortisolism with rapid onset, reversible inhibition, and minimal side effects would be ideal to address the cyclicity.

Conclusion

Our case is the first to our knowledge demonstrating osilodrostat’s use for native cyclic Cushing’s syndrome treatment and highlighted its reversibility and ability to preserve normal adrenal function.

Keywords

Osilodrostat
cyclic Cushing’s disease
cyclic Cushing’s syndrome

Introduction

Cyclic Cushing’s syndrome is a rare entity that represents a clinical challenge. It is defined by at least 3 peaks of biochemical hypercortisolism, which is clinically symptomatic in the majority though rarely asymptomatic, and 2 troughs with normalized cortisol production that can last from days to years.1 The phenomenon can arise from any potential source of Cushing’s syndrome, including pituitary (54%), ectopic (26%), adrenal (11%), and unclassified (9%) sources.1 Intermittent hypercortisolism can also occur after pituitary surgery for Cushing’s disease.2
The cyclicity interferes with a straightforward diagnosis. It can lead to paradoxical results from biochemical testing and inferior petrosal sinus sampling (IPSS),3 making determination of therapeutic outcomes more complicated.3 The goal of cyclic Cushing’s syndrome management, as in all types of Cushing’s syndrome, is early diagnosis and intervention to reduce the length of hypercortisolism.4 A surgical cure is preferred, as Cushing’s syndrome is associated with a five-fold increased standardized mortality risk.4 Cardiovascular, metabolic, bone, and cognitive comorbidities may persist despite remission and must be aggressively managed.4,5 For patients in whom surgical management is not possible or has not led to remission, medical therapy has a crucial role. We describe the first case to our knowledge of native cyclic Cushing’s syndrome treated successfully with osilodrostat. A case of exogenous cyclic ACTH-independent Cushing’s syndrome from pembrolizumab, with cyclicity attributed to the infusions, also demonstrated successful treatment with osilodrostat.6

Case Report

The patient was a 68-year-old male with hypertension, hyperlipidemia, and rheumatoid arthritis with a history of cyclical episodes of weight gain and facial swelling, occurring spontaneously without steroid treatments. The initial episode occurred at age 62 for 5 months, and returned at age 64 with facial swelling, buffalo hump, fatigue, proximal muscle weakness, sleep disturbances, and lower extremity edema. Laboratory tests showed the following (Table 1): 24-hour urine free cortisol >245 mcg/d (normal 11-84 mcg/d), morning adrenocorticotropic hormone (ACTH) 528.0 pg/mL (normal 7.2-63.3 pg/mL) and morning serum cortisol 91.7 mcg/dL (confirmed on dilution; normal 6.2-19.4 mcg/dL). Laboratory tests were also notable for a mildly low potassium level, low prolactin, low testosterone, and normal thyroid hormone, insulin-like growth factor-1 (IGF-1), and dehydroepiandrosterone sulfate (DHEA-S) levels. MRI pituitary without/with contrast showed no sellar and suprasellar masses. A prior CT abdomen/pelvis with contrast at age 62 noted unremarkable adrenal glands. The patient was referred for inferior petrosal sinus sampling (IPSS) (Table 2), which indicated a potential pituitary source of increased ACTH production, localized or draining to the right side. The central to peripheral gradient was >2 in the first pre-stimulation sample and >3 in all samples after providing 10mcg of desmopressin (DDAVP). There was a >1.4/1 gradient between the right and left sides, suggesting a potential pituitary source draining to the right side (Table 2). The inferior petrosal sinuses were normal and of similar size. Cushing’s symptoms receded spontaneously in 5 months, and the patient did not follow up until recurrence at age 67.

Table 1. Labs at time of onset of cyclical episodes

Empty Cell Labs at age 64 y/o (2nd episode) Labs at age 67 y/o (3rd episode)
24hr urine free cortisol level >245 mcg/24hr (normal 11-85 mcg/24hr) 12030.3 mcg/d (normal <= 60.0 mcg/d)
24hr urine creatinine 1495 mg/24hr (normal 1000-2000mg/24hr) 1868 mg/day (normal 800-2100 mg/day)
Morning ACTH 528.0 pg/mL (normal 7.2-63.3 pg/mL) 464 pg/mL (normal 6-59 pg/mL),
Morning cortisol 91.7 mcg/dL (normal 6.2-19.4 mcg/dL) 91 mcg/dL (normal 8-25 mcg/dL)
Thyroid-stimulating hormone level (TSH) 0.452 mcIU/mL (normal 0.450-4.500 mcIU/mL) 0.08 mcIU/mL (normal 0.3-4.7 mcIU/mL)
Free thyroxine (free T4) 1.34 ng/dL (normal 0.82-1.77 ng/dL) 1.30 ng/dL (normal 0.8-1.7 ng/dL)
Prolactin <1.0 ng/mL (normal 3.0-15.2 ng/mL) 8.05 ng/mL (normal 3.5-19.4 ng/mL)
Insulin-like growth factor-1 (IGF-1) 148 ng/mL (normal 64-240 ng/mL) 128 ng/mL (normal 41-279 ng/mL)_
Testosterone panel Total 66 ng/dL(11AM)
(normal 264-916 ng/dL)
Free 9.6 pg/mL (11AM)
(normal 6.6-18.1 pg/mL)		 Total 107 ng/dL (8:30AM)
(normal 300-720 ng/dL)
Bioavailable 61 ng/mL (8:30AM)
(normal 131-682 ng/mL)
Follicle-Stimulation Hormone (FSH) 3.6 mIU/mL (normal 1.6-9 mIU/mL)
Luteinizing Hormone (LH) 1.6 mIU/mL (normal 2-12 mIU/mL)
Dehydroepiandrosterone sulfate (DHEA-S) 153 mcg/dL (normal 48.9-344.2 mcg/dL)
Potassium level 3.2 mmol/L (normal 3.4-4.8 mmol/L) 3.3 mmol/L (normal 3.6-5.3 mmol/L)
Creatinine level 0.92 mg/dL (normal 0.7-1.2 mg/dL) 0.89 mg/dL (normal 0.6-1.3 mg/dL)

Table 2. Inferior Petrosal Sinus Sampling (IPSS)

Empty Cell Time Right IPS
ACTH level (normal 6-59 pg/mL)		 Left IPS
ACTH level (normal 6-59 pg/mL)		 Inferior Vena Cava ACTH level (normal 6-59 pg/mL) Serum Cortisol (normal 8-25 mcg/dL)
Baseline 1 08:25 AM 32 23 14 7
Baseline 2 08:27 AM 19 16 13 7
Desmopressin (DDAVP) 08:30 AM
Post 2 min 08:32 AM 150 34 15
Post 5 min 08:35 AM 123 32 18
Post 10 min 08:40 AM 49 26 17
Post 15 min 08:45 AM 124 31 17
Post 30 min 09:00 AM 107 28 13
*These results may indicate a pituitary source for increased ACTH production, localized or draining to the right side. There is a Central:Peripheral gradient of >2 (right IPS) in the first pre-stimulation samples and >3 in all post-desmopressin (DDAVP) 10mcg samples. If due to an adenoma, it might drain into the right given the presence of a significant (greater than 1.4/1) gradient between right and left. The inferior petrosal sinuses were of similar size and normal. These results must take into account the patient’s clinical scenario, and there are false positives and possible overlap with normal results.
*Abbreviation: min = minutes
During the third and most recent cycle of Cushing’s syndrome, laboratory tests after 1 month of symptom development showed the following (Table 1): 24-hour urine free cortisol 12030.3 mcg/d (normal <= 60.0 mcg/d), morning ACTH 464 pg/mL (normal 6-59 pg/mL), morning serum cortisol 91 mcg/dL (normal 8-25 mcg/dL), potassium level 3.3 mmol/L (normal 3.6-5.3 mmol/L), and mild leukocytosis and erythrocytosis. Repeat MRI pituitary without/with contrast showed a partially empty sella and no pituitary mass (Figure 1).

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Figure 1. MRI pituitary without/with contrast at the time of the third cyclical episode of Cushing’s disease. The MRI showed a partially empty sella with no evidence of a pituitary mass. Left) Coronal view. Right) Sagittal view.

The patient was started on osilodrostat 2mg twice daily. By week 2 of treatment, the morning cortisol level improved to 9.5 mcg/dL (8-25 mcg/dL) and potassium level normalized, though facial and body swelling persisted. Significant improvement in symptoms and fatigue were noted by week 3 of treatment with the following labs: morning ACTH 145 pg/mL (normal 6-59 pg/mL), morning serum cortisol 5.4 mcg/dL (8-25 mcg/dL), and 24-hour urine free cortisol 7 mcg/d (normal 5-64 mcg/d). The osilodrostat dose was decreased to 1mg twice daily, then 1mg daily, and stopped by 2 months of treatment after development of adrenal insufficiency (AI), which was confirmed on laboratory results (Table 3), along with corresponding symptoms of nausea, abdominal pain, low appetite, and fatigue. By that time, the facial and body swelling had also resolved. Potassium levels remained normal throughout treatment. After eight days off osilodrostat, laboratory tests showed the following: Noon ACTH 67 pg/mL (normal 6-59 pg/mL), noon serum cortisol 7.24 mcg/dL (normal 8-25 mcg/dL), and 24-hour urine free cortisol 26.2 mcg/d (normal <=60.0 mcg/d). Nearly 3 months off osilodrostat, the patient had an 11 AM ACTH of 68.9 pg/mL (normal 7.2-63.3 pg/mL) and 11AM serum cortisol level of 11.0 ug/dL (6.2-19.4 ug/dL). The clinical course is summarized in Table 3 and Figure 2. A DOTATATE-PET scan was discussed, though the patient wished to reconsider in the future given clinical response.

Table 3. Labs during treatment (Tx) with osilodrostat

Empty Cell 1 month before Tx Week 2 on Tx Week 3 on Tx Week 7 on Tx Week 9 on Tx – Tx stopped Week 1 off Tx Month 3 off Tx
Treatment with osilodrostat None On 2mg BID since Week 0 of Tx Advised to decrease to 1mg BID but patient did not decrease dose. Decreased to 1mg BID Decreased to 1mg daily after serum lab resulted. Then discontinued Tx after 24hr UFC resulted in several days. None None
ACTH level (pg/mL) 464 145 126 135 67 68.9
Cortisol level (mcg/dL) 91
8:32AM		 9.5
7:04AM		 5.4
7:11AM		 3.04
11:56AM		 4.9
11:26AM		 7.24
12:14PM		 11
11:08AM
24hr urine free cortisol (UFC) level (mcg/day) 12030.3 7 14 26.2
*Normal reference ranges depending on assays:
ACTH: 6-59 pg/mL or 7.2-63.3 pg/mL
Serum morning cortisol: 8-25 mcg/dL or 6.2-19.4 mcg/dL
24hr urine free cortisol: <=60.0 mcg/day or 5-64 mcg/day
*Acronyms: Tx = treatment; BID = twice daily; UFC = urine free cortisol, ACTH = adrenocorticotropic hormone

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Figure 2. Trends of 24hr urine cortisol levels and serum cortisol levels with osilodrostat treatment (Tx)

Discussion

Cyclic Cushing’s syndrome is a rare subtype of Cushing’s and occurs in both ACTH-dependent and ACTH-independent cases.3,7 Cyclicity has been attributed to hypothalamic dysfunction exaggerating a normal variant of hormonal cyclicity, a dysregulated positive feedback mechanism followed by negative feedback, intra-tumoral bleeding, and ACTH-secretion from neuroendocrine tumors (ex carcinoid tumors, pheochromocytomas).7,8,9,10
Potentially curative pituitary surgery or unilateral adrenalectomy are the treatments of choice.4 For example, cases of cyclic Cushing’s in primary pigmented nodular adrenocortical disease have demonstrated cure in some patients with unilateral adrenalectomy.11 In florid Cushing’s syndrome that is not amenable or responsive to other treatments, bilateral adrenalectomy could be lifesaving, though risks significant comorbidities including Nelson’s syndrome.4,12 Pituitary radiotherapy/radiosurgery are treatment options, though risks progressive anterior pituitary dysfunction.4 Medical therapy can play an important role as a bridge to surgery or radiation, with recurrence, for poor surgical candidates, or when there is no identifiable source as in our patient.13 Cyclic Cushing’s syndrome, moreover, has a higher recurrence rate (63%) and lower remission rate (25%), compared to classic Cushing’s syndrome.8
Medical treatments of cyclic Cushing’s syndrome include steroidogenesis inhibitors (ketoconazole, levoketoconazole, metyrapone, and osilodrostat), adrenolytic agents (mitotane), glucocorticoid receptor blockers (mifepristone), and pituitary tumor-directed agents (pasireotide, cabergoline, and temozolomide).8,14,15 Treatment goal is normalization of 24-hour urine cortisol levels and morning serum cortisol levels, though block-and-replace regimens occasionally are used.13,14 A block-and-replace regimen with osilodrostat and dexamethasone was used in the case of exogenous cyclic Cushing’s from pembrolizumab, given need for the immunotherapy;6 however, this regimen would hinder assessment of remission in native cyclic Cushing’s.
As our patient had cyclic Cushing’s disease, pituitary tumor-directed medications could be used for treatment. Pasireotide and cabergoline, however, are limited by a significant percentage of non-responders, along with risk of hyperglycemia for pasireotide.15 We considered mifepristone, which is a competitive antagonist at the glucocorticoid receptor and progesterone receptor; however, mifepristone is limited by the inability to directly monitor cortisol response on labs, in addition to the risk of AI and mineralocorticoid side effects with overtreatment.16
Steroidogenesis inhibitors block one or more enzymes in the production of cortisol, with potential risk of AI. The new steroidogenesis inhibitor osilodrostat, like metyrapone, selectively inhibits CYP11B1 and CYP11B2, which are involved in the final steps of cortisol and aldosterone synthesis, respectively.13,14 Ketoconazole and levoketoconazole, on the other hand, block most enzymes in the adrenal steroidogenesis pathway, including CYP11B1 and CYP11B2, and are limited by their inhibition of CYP7A (with associated hepatotoxicity) and strong inhibition of cytochrome p450 CYP3A4 (leading to many drug-drug interactions, decreased testosterone production, and QTc prolongation).14
Osilodrostat and metyrapone do not affect CYP7A and less potently inhibit CYP3A4.13 However, they can lead to increased deoxycorticosterone levels, with associated risks of hypokalemia, hypertension, and edema, and increased androgen production (with metyrapone thus being considered second-line in women).13,14,17
Osilodrostat, compared to metyrapone and ketoconazole, has a higher potency in CYP11B1 and CYP11B2 inhibition and a longer half-life, with stronger effects in lowering cortisol levels, allowance of less frequent (twice daily) dosing, and possibly less side effects.13,14,17,18 Compared to metyrapone, studies have suggested osilodrostat leads to a lesser rise in 11-deoxycortisol levels and less hyperandrogenic effects.13,14 Osilodrostat is also rapidly absorbed with sustained efficacy up to 6.7 years.17,18 Though rare cases of prolonged AI following discontinuation exist, osilodrostat (like other steroidogenesis inhibitors) is generally considered a reversible inhibitor.19 Reversible inhibition of cortisol synthesis is particularly appealing to treatment of cyclic Cushing’s syndrome as patients will not suffer from prolonged AI after episodes subside.
We thus considered osilodrostat an attractive treatment of cyclic Cushing’s syndrome. In our patient, osilodrostat was efficacious and well-tolerated, consistent with the literature,17 with clinical effects within 2-3 weeks without significant mineralocorticoid side effects. Differentiation of AI as a side effect of osilodrostat or from remission of the cyclical episode is crucial. Our patient was carefully tapered off osilodrostat after developing AI, and reversal of AI and osilodrostat inhibition were clearly demonstrated after 8 days off osilodrostat. Off treatment, the patient demonstrated neither prolonged AI nor clinical hypercortisolism, confirming remission of cyclic Cushing’s.

Conclusion

We present the first case to our knowledge demonstrating successful treatment of cyclic Cushing’s syndrome with osilodrostat. Osilodrostat showed rapid and safe control of hypercortisolism and importantly exhibited quick reversible inhibition of steroidogenesis upon discontinuation, a virtue in cyclic Cushing’s syndrome management.

References

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The authors declare the following:
This paper did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
All authors do not have any conflicts of interests regarding the manuscript.
Run Yu, MD, PhD runyu@mednet.ucla.edu
Clinical Relevance
Osilodrostat is a new steroidogenesis inhibitor. Our case demonstrates the first successful treatment of native cyclic Cushing’s syndrome with osilodrostat, which showed rapid onset/offset, clinical safety, and reversible inhibition of steroidogenesis and medication-induced adrenal insufficiency. Osilodrostat’s preservation of underlying adrenal function is key when the cyclic Cushing’s episode spontaneously remits.

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