Enhanced Radiological Detection of a Corticotroph Adenoma Following Treatment With Osilodrostat

Posted on October 28, 2025 by MaryO

Abstract

In approximately 30% of patients with Cushing disease, pituitary magnetic resonance imaging (MRI) does not reliably identify a corticotroph adenoma. Importantly, surgical remission rates are >2.5 fold higher for microadenomas that are radiologically visible on preoperative imaging when compared with “MRI-negative” cases. We describe a 42-year-old woman with Cushing disease, in whom MRI findings at presentation were equivocal with no clear adenoma visualized. She was initially treated with metyrapone, which resulted in partial biochemical control of hypercortisolism. After switching to osilodrostat, there was a marked improvement in her symptoms and rapid normalization of cortisol levels. Following 3 months of eucortisolemia, [11C]methionine positron emission tomography (MET-PET) coregistered with volumetric MRI (MET-PET/MRCR) localized the site of the corticotroph tumor and the patient underwent successful transsphenoidal resection. She remains in full clinical and biochemical remission at >2 years postsurgery. This case suggests that a period of eucortisolemia induced by osilodrostat may facilitate localization of corticotroph microadenomas using functional (PET) imaging.

Cushing disease, osilodrostat, [11C]methionine PET, corticotroph adenoma
Issue Section:

Case Report

Introduction

Cushing disease, caused by an ACTH-secreting pituitary adenoma, accounts for approximately 80% of endogenous Cushing syndrome [1]. Although transsphenoidal surgery remains the preferred treatment for the majority of patients, even in expert centers recurrence rates as high as 27% have been reported [2, 3]. Surgery is preferred over medical therapy because it offers the potential for definitive cure by directly removing the pituitary adenoma. In contrast, medical therapy is typically reserved for patients in whom surgery is contraindicated, incomplete, or has failed to achieve remission. Linked to this, magnetic resonance imaging (MRI) fails to detect an adenoma in approximately one third of cases [4]. In a recent systematic review, postsurgical remission rates were 2.63-fold higher (95% CI, 2.06-3.35) for MRI-detected corticotroph adenomas when compared with “MRI-negative” cases [5]. Several alternative magnetic resonance sequences have therefore been proposed to aid tumor localization (including dynamic and volumetric [eg, gradient recalled echo MRI]), but these still fail to detect a significant proportion of microcorticotropinomas [6, 7]. Accordingly, molecular (functional) imaging with positron emission tomography (PET) radiotracers that target key properties of corticotroph adenomas (eg, [11C]methionine [MET-PET], [18F]fluoroethyltyrosine, or [68Ga]DOTA-corticotropin-releasing hormone PET) has been proposed as an additional tool for localizing corticotroph tumors that evade detection on conventional MRI [6-10].

Medical therapy is often required for patients in whom surgery is not an immediate option or when there is persistent hypercortisolism postoperatively [11]. Cortisol-lowering treatment may also be considered before surgery to reduce morbidity and perioperative complications [11]. An important recent addition to the armory of medications used to treat Cushing syndrome is osilodrostat, a potent oral inhibitor of the key adrenal steroidogenic enzyme 11β-hydroxylase [12, 13].

Here, we describe how preoperative medical therapy with osilodrostat yielded dual benefits in a patient with inconclusive primary imaging: (1) rapid and effective control of hypercortisolism and (2) facilitation of the localization of a previously occult microcorticotroph adenoma using MET-PET coregistered with volumetric MRI (MET-PET/MRCR).

Case Presentation

A 42-year-old woman presented with a 7-year history of progressive central weight gain, facial plethora, acne, worsening hypertension, depression, and proximal myopathy. Her symptoms had become more pronounced during the COVID-19 pandemic, leading to profound emotional distress and functional decline. She described feeling persistently tearful and fatigued, with markedly reduced energy levels that rendered her unable to work or care for her young child, and severely affecting her quality of life. She had no significant medical history and was taking amlodipine and the progesterone-only pill. On examination, her body mass index was 29.6 kg/m² and blood pressure was markedly elevated at 197/111 mm Hg. Clinical features consistent with hypercortisolism included easy bruising, centripetal adiposity, and proximal muscle wasting. Initial laboratory evaluation was unremarkable; however, her hemoglobin A1c was at the upper end of normal (41 mmol/mol or 5.9%).

Diagnostic Assessment

Biochemical testing confirmed ACTH-dependent Cushing syndrome (Table 1). Cortisol levels following overnight and 48-hour dexamethasone suppression were elevated at 8 µg/dL (SI: 219 nmol/L) and 16 µg/dL (SI: 434 nmol/L), respectively (reference range: < 1.8 µg/dL [SI: < 50 nmol/L]). Plasma ACTH concentrations ranged from 36 to 55 ng/L (SI: 7.9-12.1 pmol/L) (reference range: 10-30 ng/L [SI: 2.2-6.6 pmol/L]), consistent with an ACTH-driven process. Urinary free cortisol (UFC) was markedly elevated at 690.95 µg/24 hours (SI: 1907 nmol/24 hours) (reference range: 18-98 µg/24 hours [SI: 50-270 nmol/24 hours]). Late-night salivary cortisol and cortisone levels were also elevated at 0.95 µg/dL (SI: 26.2 nmol/L) (reference range: < 0.09 µg/dL [SI: < 2.6 nmol/L]) and 2.7 µg/dL (SI: 74.5 nmol/L) (reference range: < 0.7 µg/dL [SI: < 18 nmol/L]) respectively. Inferior petrosal sinus sampling excluded an ectopic source of ACTH production (central-to-peripheral ACTH ratio: baseline 18.60, 0 minutes 18.4, peak at 2 minutes 94.9, 5 minutes 42.4, 10 minutes 22.3) (Table 2). However, pituitary MRI findings were inconclusive, with no definite adenoma identified. In addition, the left intracavernous carotid artery encroached medially, creating a narrow intercarotid window with distortion of normal pituitary anatomy (Fig. 1). Given these findings, the decision was made to initiate cortisol-lowering therapy and to reassess imaging appearances after a period of biochemical normalization.

Pituitary MRI at initial presentation. No discrete adenoma is visible on T1-weighted coronal precontrast (A) and postcontrast (B), T2-weighted coronal (C), and T1-weighted sagittal postcontrast (D) sequences. The sellar anatomy appears asymmetric, consistent with a medially positioned left internal carotid artery.

Figure 1.

Pituitary MRI at initial presentation. No discrete adenoma is visible on T1-weighted coronal precontrast (A) and postcontrast (B), T2-weighted coronal (C), and T1-weighted sagittal postcontrast (D) sequences. The sellar anatomy appears asymmetric, consistent with a medially positioned left internal carotid artery.

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Table 1.

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Biochemical investigations at diagnosis confirming ACTH-dependent Cushing syndrome

Tests Results Reference Range
Overnight dexamethasone suppression test (ONDST) Cortisol: 8 µg/dL (SI: 219 nmol/L) <1.8 µg/dL (SI: < 50 nmol/L)
48-hour dexamethasone suppression test (DST) Cortisol: 16 µg/dL (SI: 434 nmol/L) <1.8 µg/dL (SI: < 50 nmol/L)
ACTH 36-55 ng/L (SI: 7.9-12.1 pmol/L) 10-30 ng/L (SI: 2.2-6.6 pmol/L)
24-hour urinary free cortisol (UFC) 690.95 μg/24 h (SI: 1907 nmol/24 h) 18-98 µg/24 h (SI: 50-270 nmol/24 hours)
Late-night salivary cortisol
late-night salivary cortisone		 0.95 µg/dL (SI: 26.2 nmol/L)
2.7 µg/dL (SI: 74.5 nmol/L)		 <0.09 µg/dL (SI: <2.6 nmol/L) <0.7 µg/dL (SI: <18 nmol/L)

Results are reported in both conventional and SI units with reference ranges shown in parentheses.

Table 2.

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Results of inferior petrosal sinus sampling (IPSS)

Time Plasma ACTH
(min) Left petrosal sinus Right petrosal sinus Peripheral vein
−5 1159 ng/L (255 pmol/L) 144 ng/L (32 pmol/L) 62.3 ng/L (14 pmol/L)
0 1147 ng/L (253 pmol/L) 222 ng/L (49 pmol/L) 62.3 ng/L (14 pmol/L)
2 5257 ng/L (1157 pmol/L) 2159 ng/L (475 pmol/L) 55.4 ng/L (12.2 pmol/L)
5 3677 ng/L (810 pmol/L) 2976 ng/L (655 pmol/L) 86.8 ng/L (19 pmol/L)
10 2251 ng/L (496 pmol/L) 545 ng/L (120 pmol/L) 101 ng/L (22 pmol/L)

Time Plasma cortisol
(min) Left petrosal sinus Right petrosal sinus Peripheral vein
−5 24.94 μg/dL (668 nmol/L) 25.30 μg/dL (698 nmol/L) 23.56 μg/dL (650 nmol/L)
0 25.08 μg/dL (692 nmol/L) 24.07 μg/dL (664 nmol/L) 23.34 μg/dL (644 nmol/L)
2 23.31 μg/dL (643 nmol/L) 24.32 μg/dL (671 nmol/L) 23.78 μg/dL (656 nmol/L)
5 21.97 μg/dL (606 nmol/L) 23.67 μg/dL (653 nmol/L) 23.23 μg/dL (641 nmol/L)
10 27.62 μg/dL (762 nmol/L) 26.17 μg/dL (722 nmol/L) 25.26 μg/dL (697 nmol/L)

Time Plasma prolactin
(min) Left petrosal sinus Right petrosal sinus Peripheral vein
−5 1835 mU/L (86 μg/L) 356 mU/L (17 μg/L) 251 mU/L (11 μg/L)
0 1725 mU/L (81 μg/L) 498 mU/L (23 μg/L) 248 mU/L (12 μg/L)
2 2151 mU/L (101 μg/L) 409 mU/L (19 μg/L) 240 mU/L (11 μg/L)
5 2239 mU/L (105 μg/L) 711 mU/L (33 μg/L) 246 mU/L (12 μg/L)
10 1883 mU/L (89 μg/L) 410 mU/L (19 μg/L) 244 mU/L (11 μg/L)

Central-to-peripheral ACTH gradients before and after corticotropin-releasing hormone (CRH) stimulation support a pituitary source of ACTH secretion. Reference cutoffs: basal ACTH gradient ≥2 and/or CRH-stimulated ACTH gradient ≥3 indicate central ACTH secretion.

Treatment

The patient was started on metyrapone, but despite dose escalation up to 4000 mg daily, which was associated with significant nausea and malaise, she did not achieve eucortisolemia (Fig. 2C). She was therefore transitioned to osilodrostat, which rapidly normalized cortisol levels within 5 weeks at a maintenance dose of 6 mg twice daily (Fig. 2B and 2C). In contrast to metyrapone, osilodrostat was well-tolerated with no reported side effects. Serum cortisol and clinical status were closely monitored throughout, with no biochemical or clinical evidence of adrenal insufficiency.

Bar charts illustrating changes in urinary, salivary, and serum cortisol, as well as serum ACTH, during medical treatment. (A) A 24-hour UFC (black bars, left y-axis) normalized during osilodrostat treatment, whereas serum ACTH (gray bars, right y-axis) increased. Dotted lines represent the upper limit of normal: 59.4 µg/24 hours (SI: 164 nmol/24 hours) for UFC and 30 ng/L (SI: 6.6 pmol/L) for ACTH. X-axis labels indicate treatment week and total daily osilodrostat dose. (B) Salivary free cortisol levels, collected alongside serum cortisol during a cortisol day curve (at 09:00, 12:00, 15:00, and 18:00), fully normalized with osilodrostat therapy. Bar shading from black to light gray denotes sampling time. The dotted line indicates upper limit of normal: 9.4 ng/dL (SI: 2.6 nmol/L). (C) Serum free cortisol levels during day curves showed inadequate control on escalating doses of metyrapone, with normalization achieved following initiation of osilodrostat.

Figure 2.

Bar charts illustrating changes in urinary, salivary, and serum cortisol, as well as serum ACTH, during medical treatment. (A) A 24-hour UFC (black bars, left y-axis) normalized during osilodrostat treatment, whereas serum ACTH (gray bars, right y-axis) increased. Dotted lines represent the upper limit of normal: 59.4 µg/24 hours (SI: 164 nmol/24 hours) for UFC and 30 ng/L (SI: 6.6 pmol/L) for ACTH. X-axis labels indicate treatment week and total daily osilodrostat dose. (B) Salivary free cortisol levels, collected alongside serum cortisol during a cortisol day curve (at 09:00, 12:00, 15:00, and 18:00), fully normalized with osilodrostat therapy. Bar shading from black to light gray denotes sampling time. The dotted line indicates upper limit of normal: 9.4 ng/dL (SI: 2.6 nmol/L). (C) Serum free cortisol levels during day curves showed inadequate control on escalating doses of metyrapone, with normalization achieved following initiation of osilodrostat.

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ACTH levels progressively increased as the dose of osilodrostat was escalated (Fig. 2A). After 3 months of biochemical eucortisolism, she underwent Met-PET/MRCR, which revealed a distinct methionine-avid lesion in the right posterolateral aspect of the sella (Fig. 3). Imaging was performed as previously reported [7, 8, 14]. Conventional MRI findings remained stable, with no new abnormalities. As she remained clinically and biochemically eucortisolemic on osilodrostat, glucocorticoid supplementation was not required pre- or perioperatively.

11C-Methionine PET/CT coregistered with volumetric MRI (MET-PET/MRCR) following treatment with osilodrostat. A subtle area of reduced gadolinium enhancement can now be appreciated on the right posterosuperior aspect of the gland (A-C). MET-PET/MRCR confirms focal tracer uptake at this site (yellow arrows) and also within normal gland anteriorly (white arrow) (D-F). Three-dimensional reconstruction using CT, MRI, and PET datasets demonstrating the location of the corticotroph microadenoma which was confirmed at subsequent surgery (G-H).

Figure 3.

11C-Methionine PET/CT coregistered with volumetric MRI (MET-PET/MRCR) following treatment with osilodrostat. A subtle area of reduced gadolinium enhancement can now be appreciated on the right posterosuperior aspect of the gland (A-C). MET-PET/MRCR confirms focal tracer uptake at this site (yellow arrows) and also within normal gland anteriorly (white arrow) (D-F). Three-dimensional reconstruction using CT, MRI, and PET datasets demonstrating the location of the corticotroph microadenoma which was confirmed at subsequent surgery (G-H).

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Outcome and Follow-up

At transsphenoidal surgery, abnormal tissue was resected from the site identified on MET-PET/MRCR. Histological examination revealed normal anterior pituitary tissue (adenohypophysis) with no evidence of a pituitary adenoma. Occasional cells showed possible Crooke’s hyaline change. The Ki-67 proliferation index was very low (<1%). Despite the absence of histological confirmation of a corticotroph adenoma, the patient entered complete biochemical and clinical remission. Early postoperative cortisol was 3 µg/dL (SI: 82.8 nmol/L), prompting initiation of glucocorticoid replacement with prednisolone. Prednisolone was chosen for its longer half-life, enabling convenient once-daily dosing. We routinely monitor prednisolone levels to guide adjustment of replacement dosing. Prednisolone was successfully tapered over a period of 6 months, with biochemical confirmation of adrenal recovery. At 2 years postsurgery, the patient had no clinical features of hypercortisolism with sustained weight loss of >20 kg. Morning 09:00 cortisol and ACTH were consistent with ongoing eucortisolism. Serial late-night salivary cortisol and cortisone levels were normal, and cortisol was undetectable following a 1-mg overnight dexamethasone suppression test, confirming durable remission of Cushing disease.

Discussion

Early transsphenoidal surgery remains the treatment of choice for most patients with Cushing disease, with the highest chance of cure achieved following a successful first operation [11]. However, even in expert centers, persistent or recurrent disease is diagnosed during follow-up, and is more likely when initial MRI has failed to identify a clear surgical target [5]. Reoperation carries increased technical difficulty and a higher risk of iatrogenic hypopituitarism, underscoring the importance of accurate preoperative localization of corticotroph adenomas. Our case illustrates a potential novel added benefit of a trial of primary medical therapy in a patient with Cushing disease and equivocal or negative MRI findings at initial presentation. Specifically, we have shown how osilodrostat, a potent inhibitor of 11β-hydroxylase, can achieve rapid normalization of cortisol levels, consistent with the findings of the LINC (LCI699 [osilodrostat] in Cushing disease) series of studies [15-17], and at the same time help reveal the location of the occult microcorticotropinoma. An important consequence of achieving effective adrenal blockade in our patient was the more than threefold accompanying rise in plasma ACTH levels (Fig. 2). We hypothesized that such an increase in tumoral activity might facilitate its detection using molecular (functional) imaging. MET-PET has been shown in several studies to facilitate localization of de novo and recurrent corticotroph adenomas [8, 18, 19] in a significant proportion of patients with equivocal or negative MRI findings. We have now shown that such an approach could potentially be enhanced by pretreatment with the potent 11β-hydroxylase inhibitor osilodrostat.

We also considered whether the rise in ACTH during osilodrostat therapy reflected increased tumor activity alone or was associated with a change in tumor size. In our case, ACTH rose significantly, likely reflecting enhanced secretory activity, whereas repeat conventional MRI remained stable, with no new abnormalities or interval changes. In the LINC 4 study, tumor volume data were available for 35 patients at both baseline and week 48. Among these, 40.0% had a ≥20% increase, 28.6% had a ≥20% decrease, and 31.4% had <20% change in tumor volume. These outcomes were observed in both microadenomas and macroadenomas, with no clear correlation to treatment duration or osilodrostat dose [20]. This variability suggests that osilodrostat does not exert a consistent effect on tumor volume.

Interestingly, although histopathological analysis did not confirm a corticotroph adenoma, this is a well-recognized finding and has been reported in a significant proportion of patients undergoing surgery for Cushing disease [21, 22]. Nonetheless, we consider the diagnosis of pituitary-dependent Cushing syndrome was clearly established by the clinical features, results of initial laboratory testing and findings at inferior petrosal sinus sampling (which demonstrated a clear central-to-peripheral ACTH gradient). In addition, abnormal tissue was identified intraoperatively at the site visualized on MET-PET and fully resected, and no other abnormal foci of tissue were seen. The patient has subsequently achieved complete and sustained clinical and biochemical remission, consistent with successful removal of an ACTH-secreting adenoma.

Recent case reports have raised concerns about prolonged adrenal insufficiency following extended osilodrostat use—an unexpected finding given the drug’s short half-life [23-25]. Although adrenal insufficiency requiring temporary glucocorticoid replacement had been reported in clinical trials (most commonly in patients undergoing rapid dose escalation [12, 15, 16]), prolonged hypothalamopituitary-adrenal axis suppression resulting from supraphysiologic glucocorticoid replacement could also be contributory. For now, the exact mechanism of this observed phenomenon remains unclear. Our patient managed to wean glucocorticoid replacement postoperatively and did not demonstrate prolonged adrenal suppression; at the same time, clinical and biochemical testing confirmed full remission from Cushing disease.

This case supports the hypothesis that preoperative cortisol suppression may enhance the diagnostic accuracy of molecular (functional) imaging in Cushing disease, particularly in cases with inconclusive MRI findings. If validated in prospective studies, this approach could refine surgical planning and potentially lead to better surgical success and durable clinical outcomes.

Learning Points

  • Approximately 30% of corticotroph adenomas causing Cushing disease are not readily localized on conventional pituitary MRI.

  • Functional imaging modalities such as MET-PET/MRCR can improve detection of previously occult pituitary adenomas in Cushing disease.

  • A period of medical pretreatment with osilodrostat, with consequent reduction in negative feedback by glucocorticoid at the hypothalamic-pituitary level, may augment tumor localization by molecular imaging.

Acknowledgments

The authors acknowledge Debbie Papadopoulou and Niamh Martin for their contributions to clinical management. Nigel Mendoza performed the transsphenoidal surgery.

Contributors

All authors made individual contributions to authorship. Z.H., L.Y., J.M., M.G., and F.W. were involved in the diagnosis and management of this patient and manuscript submission. J.M., D.G., and M.G. performed and analyzed the patient’s functional imaging. All authors reviewed and approved the final draft.

Funding

No public or commercial funding

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Original data generated and analyzed during this study are included in this published article.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.

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Improved Noninvasive Diagnostic Evaluations in Treatment-Naïve Adrenocorticotropic Hormone (ACTH)-Dependent Cushing’s Syndrome

Posted on July 24, 2025 by MaryO

Abstract

Background

Bilateral inferior petrosal sinus sampling (BIPSS) is important in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome, but BIPSS is invasive and is not reliable on tumor lateralization. Thus, we evaluated the noninvasive diagnostic evaluations, high-dose dexamethasone suppression test (HDDST) combined with different pituitary MRI scans (conventional contrast-enhanced MRI [cMRI], dynamic contrast-enhanced MRI [dMRI], and high-resolution contrast-enhanced MRI [hrMRI]), by comparison with BIPSS.

Methods

We retrospectively analyzed 95 patients with ACTH-dependent Cushing’s syndrome who underwent HDDST, preoperative MRI scans (cMRI, dMRI and hrMRI) and BIPSS in our hospital between January 2016 and December 2021. The diagnostic performance of HDDST combined with cMRI (HDDST + cMRI), HDDST + dMRI and HDDST + hrMRI, and BIPSS was evaluated, including the sensitivity of identifying pituitary adenomas and the tumor lateralization accuracy.

Results

Compared with BIPSS (AUC, 0.98; 95%CI: 0.93, 1.00), the diagnostic performance of HDDST + hrMRI was comparable in both neuroradiologist 1 (AUC, 0.95; 95%CI: 0.89, 0.99; P = 0.129) and neuroradiologist 2 (AUC, 0.98; 95%CI: 0.92, 1.00; P = 0.707). For tumor lateralization accuracy, HDDST + hrMRI (90.6-95.3%) were significantly higher than that of BIPSS (24.7%, P < 0.001).

Conclusions

In patients with ACTH-dependent Cushing’s syndrome, HDDST + hrMRI, as noninvasive diagnostic evaluations, achieves high diagnostic performance comparable with gold standard (BIPSS), and it is superior to BIPSS in terms of tumor lateralization accuracy.

Peer Review reports

Background

Cushing’s syndrome is associated with debilitating morbidity and increased mortality [1]. Adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome is characterized by ACTH hypersecretion. Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as the gold standard to distinguish pituitary ACTH secretion (also known as Cushing’s disease) from ectopic ACTH syndrome (EAS) [1, 2]. However, BIPSS is invasive and is not reliable on tumor lateralization [3, 4]. Thus, it is important to improve the diagnostic performance of noninvasive evaluations with high sensitivity and tumor lateralization accuracy.

Current noninvasive evaluations in the differential diagnosis of ACTH-dependent Cushing’s syndrome include high-dose dexamethasone suppression test (HDDST), the CRH stimulation test and pituitary MRI. However, due to the non-availability of CRH for testing, the sensitivities of current available noninvasive evaluations in identifying ACTH-secreting pituitary adenomas cannot satisfy the clinical needs. Conventional contrast-enhanced MRI (cMRI) and dynamic contrast-enhanced MRI (dMRI) with two-dimensional (2D) fast spin echo (FSE) sequence is routinely used, and only 50–66% of the ACTH-secreting pituitary adenomas can be correctly detected [5, 6]. Recently, by using 3D spoiled gradient recalled (SPGR) sequence, high-resolution contrast-enhanced MRI (hrMRI) has increased the sensitivity to up to 80% [7,8,9]. However, these noninvasive evaluations are still inferior to BIPSS, the sensitivity and specificity of which is about 90–95% [10,11,12,13]. With the development of 3D FSE sequence, superior image quality with diminished artifact has been achieved, providing a reliable alternative to detect pituitary adenomas [14]. Previous studies have shown that hrMRI using 3D FSE sequence has high diagnostic performance for identifying pituitary adenomas [15, 16]. To our knowledge, no study has investigated the diagnostic performance of HDDST combined with hrMRI using 3D FSE sequence (HDDST + hrMRI) in patients with Cushing’s syndrome, and whether it can avoid unnecessary BIPSS procedure.

The aim of this study is to evaluate the diagnostic performance of HDDST + hrMRI by comparison with BIPSS in patients with ACTH-dependent Cushing’s syndrome.

Methods

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Peking Union Medical College Hospital. Informed consent was waived in this study because it was a retrospective, non-interventional, and observational study. Clinical trial number is not applicable.

Study design and patient population

We retrospectively reviewed the medical records and imaging studies from January 2016 to December 2021, and 232 consecutive patients with ACTH-dependent Cushing’s syndrome, who underwent HDDST, cMRI, dMRI, hrMRI and BIPSS, were enrolled in the current study. A total of 137 patients were excluded from the study because of prior pituitary surgery (n = 122) or lack of histopathology due to no pituitary surgery in our hospital (n = 15). Finally, 95 patients were included in the current study (Fig. 1) and all the patients included were confirmed by histopathology or by clinical remission after surgical resection of the ACTH-secreting lesion. In the current study, all the patients with Cushing’s disease achieved clinical remission after surgical resection of the ACTH-secreting lesion. All the patients with EAS underwent contrast-enhanced thoracic and abdominal CT to identify the ACTH-secreting lesion. The clinical decision-making process was consistent with the previous study [1].

Fig. 1
figure 1

Flowchart of patient inclusion/exclusion process. ACTH = adrenocorticotropic hormone, BIPSS = bilateral inferior petrosal sinus sampling; cMRI = conventional contrast-enhanced MRI, dMRI = dynamic enhanced MRI, HDDST = high-dose dexamethasone suppression test, hrMRI = high-resolution contrast-enhanced MRI, NPV = negative predictive value, PPV = positive predictive value

HDDST

As previously described [17], the average 24-hour urinary free cortisol (24hUFC) level of 2 days before HDDST was recorded as baseline. Then, 2 mg dexamethasone was administered orally every 6 h for 2 days, and the 24hUFC level of the second day was measured. When the ratio of 24hUFC on the second day after HDDST to 24hUFC at baseline was less than 50%, the suppression in HDDST was marked as positive in the current study.

BIPSS

BIPSS was performed according to Doppman et al. [18]. Blood samples were collected from peripheral veins and bilateral inferior petrosal sinuses (IPSs) at multiple time points (0, 3, 5 and 10 min) after the introduction of 10 µg desmopressin [19]. An IPS to peripheral ACTH ratio of ≥ 2.0 at baseline or ≥ 3.0 after desmopressin stimulation at any time point [20] was marked as positive in the current study. Furthermore, tumor lateralization was predicted by an intersinus ratio of ≥ 1.4 [20].

Imaging

All the images were acquired on a 3.0 Tesla MR scanner (Discovery MR750w, GE Healthcare) using an 8-channel head coil. Detailed acquisition parameters and sequence order before and after contrast injection (gadopentetate dimeglumine [Gd-DTPA] at 0.05 mmol/kg [0.1 mL/kg] with a flow rate of 2 mL/s followed by a 10-mL saline solution flush) were as follows: coronal 2D FSE T2WI (field of view [FOV] = 20 cm × 20 cm, slice thickness = 4 mm, slice spacing = 1 mm, repetition time/echo time [TR/TE] = 4100/90 ms, number of excitation [NEX] = 1.2, matrix = 320 × 320, scan time = 49s), coronal 2D FSE T1WI (FOV = 18 cm × 16.2 cm, slice thickness = 3 mm, slice spacing = 0.6 mm, TR/TE = 400/12 ms, NEX = 2, matrix = 256 × 192, scan time = 49s), sagittal fat-saturated 3D FSE T1WI (FOV = 16.5 cm × 16.5 cm, slice thickness = 3 mm, slice spacing = 0, TR/TE = 460/16 ms, NEX = 2, matrix = 256 × 224, scan time = 60s), dynamic contrast-enhanced coronal 2D FSE T1WI (FOV = 19 cm × 17.1 cm, slice thickness = 2 mm, slice spacing = 0.5 mm, TR/TE = 375/14 ms, NEX = 1, matrix = 288 × 192, scan time = 23s/phase × 6 phases), contrast-enhanced coronal 2D FSE T1WI, contrast-enhanced sagittal fat-saturated 3D FSE T1WI, and contrast-enhanced coronal fat-saturated 3D FSE T1WI (FOV = 15.2 cm × 15.2 cm, slice thickness = 1.2 mm, slice spacing = -0.6 mm, TR/TE = 390/15 ms, NEX = 6, matrix = 256 × 256, scan time = 4 min 30s).

Images were independently evaluated by two experienced neuroradiologists (with 25 and 16 years of experience in neuroradiology, respectively). Both neuroradiologists were blinded to the clinical information of the patients. The image order of cMRI, dMRI and hrMRI was randomized. The detection of pituitary adenomas was scored using a 3-point scale (0 = poor, 1 = fair, 2 = excellent). Scores of 1 or 2 represented a successful pituitary adenoma detection. The gold standard was the histopathology, and the diameter and the location of lesions were recorded on the sequence where identified.

The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated as follows: SNR = SIadenoma / SDbackground, CNR = |SIpituitary – SIadenoma| / SDbackground. SIpituitary and SIadenoma were defined as the mean signal intensity of the pituitary gland and the pituitary adenoma, respectively. SDbackground was defined as the standard deviation of the signal intensity of the background. CNR was recorded as 0 when no pituitary adenoma was identified. Figure 2 showed the calculation of SNR and CNR using an operator defined region of interest.

Fig. 2

figure 2

The calculation of SNR and CNR using an operator defined region of interest. CNR = contrast-to-noise ratio, SD = standard deviation, SI = signal intensity, SNR = signal-to-noise ratio

Statistical analysis

The κ analysis was conducted to assess the interobserver agreements. The κ value was interpreted as follows: below 0.20, slight agreement; 0.21–0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, substantial agreement; greater than 0.80, almost perfect agreement.

To assess the diagnostic performance of different evaluations, the receiver operating characteristic curves were plotted and the area under curves (AUCs) were compared between noninvasive and invasive evaluations for each neuroradiologist by using the DeLong test. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. The Friedman’s test was used to evaluate the SNR and CNR measurements as well as conspicuity scores of pituitary adenomas between MR protocols, and the Wilcoxon signed-rank test was used for pairwise comparison. The McNemar’s test was used to evaluate the tumor lateralization accuracy. A P value of less than 0.05 was considered statistically significant. A stricter P value of less than 0.017 was considered statistically significant after Bonferroni correction. Statistical analysis was performed using MedCalc Statistical Software (version 23.0.2) and SPSS Statistics (version 22.0).

Results

Clinical characteristics

The clinical characteristics of the 95 patients with Cushing’s syndrome were shown in Table 1. There were 85 patients (median age, 38 years; interquartile range [IQR], 29–51 years; 55 females [65%]) with Cushing’s disease and 10 patients (median age, 39 years; IQR, 30–47 years; 5 females [50%]) with EAS. Of the 85 patients with Cushing’s disease, the median diameter of pituitary adenomas was 5 mm (IQR, 4–5 mm), ranging from 3 to 28 mm. Among them, 80 patients had microadenomas (less than 10 mm in size). Of the ten patients with EAS, one patient had an ovarian carcinoid tumor found by abdominal CT, others had pulmonary carcinoid tumors found by thoracic CT as the cause of Cushing’s syndrome. None of the patients with EAS had a lesion in the pituitary.

Table 1 Clinical characteristics of the patients

Diagnostic performance noninvasive and invasive evaluations

The inter-observer agreements between two neuroradiologists were moderate on cMRI (κ = 0.597), moderate on dMRI (κ = 0.595), and almost perfect on hrMRI (κ = 0.850), respectively.

The diagnostic performance of noninvasive and invasive evaluations was shown in Table 2. Compared with BIPSS (AUC, 0.98; 95%CI: 0.93, 1.00), the diagnostic performance of HDDST + hrMRI was comparable in both neuroradiologist 1 (AUC, 0.95; 95%CI: 0.89, 0.99; P = 0.129) and neuroradiologist 2 (AUC, 0.98; 95%CI: 0.92, 1.00; P = 0.707). However, the diagnostic performance of HDDST + cMRI and HDDST + dMRI was inferior to BIPSS (P ≤ 0.001 for all). No difference was found between HDDST + cMRI and HDDST + dMRI in neuroradiologist 1 (P = 0.050) and neuroradiologist 2 (P = 0.353).

Table 2 The diagnostic performance of noninvasive and invasive evaluations

Figures 3 and 4 showed that microadenomas were correctly diagnosed on hrMRI, but missed on cMRI or dMRI.

Fig. 3

figure 3

Images in a patient with Cushing’s disease. The lesion is missed on (a) coronal contrast-enhanced T1-weighted image and (b) coronal dynamic contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence. (c) Coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence shows a round pituitary microadenoma measuring approximately 4 mm with delayed enhancement on the left side of the pituitary gland

Fig. 4

figure 4

Images in a patient with Cushing’s disease. The lesion is missed on (a) coronal contrast-enhanced T1-weighted image and (b) coronal dynamic contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence. (c) Coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence shows a round pituitary microadenoma measuring approximately 5 mm with delayed enhancement on the left side of the pituitary gland

Further, subgroup analysis was conducted in 85 patients with Cushing’s disease. The conspicuity scores of pituitary adenomas on cMRI, dMRI and hrMRI were shown in Table 3. Significant differences between three MR protocols were found in neuroradiologist 1 and neuroradiologist 2 (P < 0.001 for both). Pairwise comparison showed no difference between cMRI and dMRI in neuroradiologist 1 (P = 0.732) and neuroradiologist 2 (P = 0.130). However, hrMRI had significantly higher scores than cMRI and dMRI in neuroradiologist 1 and neuroradiologist 2 (P < 0.001 for all). The SNR on cMRI, dMRI and hrMRI were 64.8 (IQR, 50.8–97.0), 42.4 (IQR, 30.2–57.0) and 65.1 (IQR, 51.9–92.4), respectively. The SNR on cMRI and hrMRI were similar (P = 0.759), but they were higher than that of dMRI (P < 0.001 for both). The CNR on cMRI, dMRI and hrMRI were27.0 (IQR, 17.8–43.8), 26.4 (IQR, 17.7–37.5), and 29.7 (IQR, 21.1–45.1), respectively. The CNR were comparable (P = 0.159).

Table 3 Conspicuity scores of pituitary adenomas on MRI

The comparison of tumor lateralization accuracy was shown in Table 4. Because HDDST has no role to identify the tumor lateralization, the tumor lateralization of noninvasive evaluations was only based on MRI. The sensitivity of BIPSS was 96.5% (82/85), comparable to those of hrMRI in neuroradiologist 1 (90.6%, P = 0.227) and neuroradiologist 2 (95.3%, P > 0.99). However, for tumor lateralization accuracy, 36 patients had BIPSS lateralization predicted by an intersinus ratio of ≥ 1.4 [20], and 21 patients had BIPSS lateralization that were concordant in laterality with surgery. The tumor lateralization accuracy was 58.3% (21/36).

Table 4 Tumor lateralization accuracy comparison

In the whole population, the tumor lateralization accuracy of BIPSS in total was 24.7% (21/85), which is significantly lower than those of hrMRI in neuroradiologist 1 (90.6%, P < 0.001) and neuroradiologist 2 (95.3%, P < 0.001).

Discussion

In patients with ACTH-dependent Cushing’s syndrome, it is crucial but challenging to distinguish pituitary secretion from ectopic ACTH secretion. In the current study, the diagnostic performance of noninvasive evaluations, HDDST + hrMRI, is comparable to BIPSS. Moreover, it is superior to BIPSS in terms of tumor lateralization.

No consensus agreement has been made that whether BIPSS should be performed in all the patients with suspected Cushing’s disease, although BIPSS is the gold standard with high sensitivity and specificity, which is about 90–95% [10,11,12,13]. On the one hand, about 10–40% of the population harbor nonfunctioning pituitary adenomas [13, 21], which may lead to false-positive results without centralizing BIPSS results. On the other hand, BIPSS is invasive and is not reliable on tumor lateralization. BIPSS will be bypassed when the tumor is greater than 6 mm in pituitary MRI and the patient has a classical presentation and dynamic biochemical results consistent with Cushing’s disease [13].

Noninvasive evaluations have comparable sensitivity to BIPSS for identifying pituitary adenomas in patients with Cushing’s disease. With the development of MRI technology, 3D FSE sequence provides a reliable alternative to detect pituitary adenomas [14]. The 3D FSE sequence overcomes the disadvantages of 3D SPGR sequence, such as bright blood and magnetic susceptibility [22, 23]. By using black blood in 3D FSE sequence, an obvious contrast between the pituitary and the cavernous sinus can be observed. By using fat saturation after enhancement, the hyperintensity of adjacent fat-containing tissue can be suppressed. All these mentioned above can facilitating the identification of pituitary adenomas. The sensitivity of hrMRI using 3D FSE sequence ranges from 87.7 to 93.8%, depending on radiologists with different experience levels [16]. Compared with traditional 2D FSE sequence acquiring images with 2- to 3-mm slice thickness, hrMRI using 3D FSE sequence acquiring images with 1.2-mm slice thickness can dramatically reduce the partial volume averaging effect, improving the identification of the microadenomas [15]. The trade-off between spatial resolution and image noise is challenging in pituitary MRI [24]. Previous studies have proved that hrMRI has high signal-to-noise ratio and contrast-to-noise ratio [15, 16], and sufficient contrast between pituitary adenomas and the pituitary gland could help to improve the identification of pituitary adenomas. In the current study, the conspicuity scores of hrMRI are significantly higher than those of cMRI and dMRI, supporting that hrMRI is reliable on identifying pituitary lesions. Besides, the diagnosis of Cushing’s disease cannot be made depending on the results of hrMRI alone. Given that there is a population with accidental adenomas when imaging, most of which are nonfunctioning pituitary adenomas, the results of HDDST will help rule out. In the current study, all the patients who underwent surgery had positive histopathology results, which means that no pituitary incidentalomas were found in this population. This might be caused by the relatively small sample size. Eighty patients with Cushing’s disease have microadenomas, and the median diameter at surgery is about 5 mm, consistent with previous studies [25, 26]. All these mentioned above makes it more difficult to identify the lesions in the current study. However, the sensitivity of HDDST + hrMRI in the current study is up to 95.3%, comparable to the gold standard.

Noninvasive evaluations have significantly higher tumor lateralization accuracy than BIPSS. According to the guideline, surgery is the first-line treatment [3]. Precise location of the pituitary adenoma before surgery can dramatically improve the postoperative remission rate [27]. However, the tumor lateralization accuracy of BIPSS, less than 80% in previous studies [19, 28, 29], cannot satisfy the clinical need. According to previous studies, the cut-off value for tumor lateralization was set as an intersinus ratio of ≥ 1.4 [20], and the accuracy of lateralization by BIPSS ranged from 48.0 to 78.7% [19, 28, 29]. In the current study, 36 patients had BIPSS lateralization and 21 patients had BIPSS lateralization that were concordant in laterality with surgery. The tumor lateralization accuracy was 58.3%, consistent with previous studies [19, 28, 29]. However, the aim of our study is to evaluate the diagnostic performance of BIPSS in all the patients underwent BIPSS, therefore, the tumor lateralization accuracy of BIPSS in total was only 24.7% (21/85). In our study, many patients have positive BIPSS results with an intersinus ratio of < 1.4, resulting in the low tumor lateralization accuracy of BIPSS. One possible reason might be that desmopressin is not so effective. Another possible reason for low tumor lateralization accuracy of BIPSS is that IPSs have considerable anatomy variations. A previous study suggests that BIPSS results are much improved when venous drainage is symmetric [30]. Patients with asymmetric IPSs have dominant venous drainage, and when the dominant side of venous drainage is discordant with the side of the lesion, BIPSS will fail in tumor lateralization [30]. Failure in tumor lateralization will result in multiple incisions into the pituitary in search of adenoma or hemi- or subtotal hypophysectomy, increasing the risk of complications and reducing the remission rate [31]. In total, only 24.7% of the patients have a BIPSS lateralization that were concordant in laterality with surgery, whereas the tumor lateralization accuracy of HDDST + hrMRI is superior to BIPSS with statistical significance.

Limitations of the study included its retrospective nature. The bias may be introduced during the patient inclusion/exclusion process. Patients lack of any of preoperative MRI scans, HDDST, or BIPSS have not been included in the current study. Some patients will bypass hrMRI as well as BIPSS when they have obvious pituitary adenomas on cMRI and dMRI. The diagnostic performance of these evaluations might be better with the inclusion of these patients. Second, the sample size in our current study is relatively small. Because this is a single institutional study and Cushing’s syndrome is a rare disease. The relatively small sample size may limit the conclusions regarding the diagnostic performance of hrMRI for differentiating ectopic from pituitary sources of ACTH. A larger population from multicenter is needed for future study. Besides, a large portion of patients with prior pituitary surgery have been excluded. The imaging findings of these patients are more complicated and hrMRI may show more advantages than routine sequences in this population.

Conclusions

In conclusion, as noninvasive diagnostic evaluations, HDDST + hrMRI achieves high diagnostic performance comparable with gold standard (BIPSS), and it is superior to BIPSS in terms of tumor lateralization accuracy in patients with ACTH-dependent Cushing’s syndrome.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

24hUFC:
24-hour urinary free cortisol
2D:
Two-dimensional
3D:
Three-dimensional
ACTH:
Adrenocorticotropic hormone
AUC:
Area under curve
BIPSS:
Bilateral inferior petrosal sinus sampling
cMRI:
Contrast-enhanced MRI
CNR:
Contrast-to-noise ratio
dMRI:
Dynamic contrast-enhanced MRI
EAS:
Ectopic adrenocorticotropic hormone syndrome
FSE:
Fast spin echo
HDDST:
High-dose dexamethasone suppression test
hrMRI:
High-resolution contrast-enhanced MRI
IPS:
Inferior petrosal sinus
IQR:
Interquartile range
SNR:
Signal-to-noise ratio
SPGR:
Spoiled gradient recalled

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Acknowledgements

We thank Dr. Kai Sun, Medical Research Center, Peking Union Medical College Hospital, for his guidance on the statistical analysis in this study. We thank all the patients who participated in this study.

Funding

This study was supported by the National Natural Science Foundation of China (grants 82371946 and 82071899), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant 2021-I2M-1-025), and the National High Level Hospital Clinical Research Funding (grants 2022-PUMCH-B-067 and 2022-PUMCH-B-114). The funding played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Author information

Authors and Affiliations

  1. Department of Radiology, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Zeyu Liu, Bo Hou, Hui You, Mingli Li & Feng Feng

  2. Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Lin Lu, Lian Duan & Huijuan Zhu

  3. Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Kan Deng & Yong Yao

  4. State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Yong Yao, Huijuan Zhu & Feng Feng

Contributions

All authors have participated sufficiently in this submission to take public responsibility for its content. H.Y. and F.F. proposed research ideas, revised the paper, and reviewed it academically. B.H. and Z.L. were responsible for literature review, data analysis and writing the manuscript. M.L. revised the paper. L.L., L.D. and H.Z. collected the clinical data. K.D. and Y.Y. collected the surgical and histopathology data. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Hui You or Feng Feng.

Ethics declarations

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Peking Union Medical College Hospital. Informed consent was waived by Institutional Review Board of Peking Union Medical College Hospital, because it was a retrospective, non-interventional, and observational study.

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Not applicable.

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The authors declare no competing interests.

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Liu, Z., Hou, B., You, H. et al. Improved noninvasive diagnostic evaluations in treatment-naïve adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome. BMC Med Imaging 25, 252 (2025). https://doi.org/10.1186/s12880-025-01786-y

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Reconstructive Liposuction for Residual Lipodystrophy After Remission of Cushing’s Disease

Posted on July 3, 2025 by MaryO

​Abstract

Cushing’s syndrome (CS) is often presented due to an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, characterized by high chronic cortisol levels. Surgical resection of the pituitary adenoma is the primary treatment, but long-term metabolic and physical sequelae can persist, affecting psychological well-being and social functioning. Glucocorticoids are directly involved in alterations of fat metabolism, favoring centripetal adiposity. Even after hormonal normalization, patients may experience residual lipodystrophy. Impairment of body image may cause psychological distress and social isolation. The objective is to illustrate the potential therapeutic value of reconstructive liposuction in restoring body image and psychological well-being in a patient with persistent lipodystrophy after Cushing’s disease remission.

We report a case of a 16-year-old female with recurrent Cushing’s disease secondary to a pituitary microadenoma, confirmed by elevated urinary free cortisol and magnetic resonance imaging (MRI). It was initially treated with transsphenoidal resection in 2019; disease recurrence was confirmed and again treated in 2024. Despite intervention, the prolonged hypercortisolism developed into secondary lipodystrophy, leading to severe body image dissatisfaction and social withdrawal. Thyroid function remained euthyroid, ruling out metabolic contributors. Because of the psychological distress caused by persistent fat redistribution, the patient underwent elective liposuction in 2025. Postoperative follow-up revealed reduced psychological distress and improved well-being and self-esteem. Reconstructive liposuction can play a key role in the treatment and management of persistent post-CS lipodystrophy, contributing significantly to psychological recovery. Prospective studies evaluating surgical criteria and long-term psychosocial outcomes are needed to define eligibility criteria and assess outcomes, leading to the development of clinical guidelines for aesthetic interventions in post-CS recovery.

Introduction

Corticotroph pituitary adenomas (corticotropinomas) are pituitary tumors that secrete excess adrenocorticotropic hormone (ACTH), causing endogenous Cushing’s syndrome (CS). Most of these adenomas are sporadic and monoclonal, although in some rare cases, they are associated with germline mutations (e.g., in USP8) or genetic syndromes [1,2]. Clinically, excess ACTH causes a classic presentation with centripetal obesity, purple striae, muscle asthenia, hypertension, and emotional disturbances such as depression or anxiety [3-5]. Chronically elevated cortisol levels promote fat deposition in central body regions – face, neck, torso, and abdomen – at the expense of relative thinning of the limbs [3], leading to lipodystrophy that can seriously affect the patient’s quality of life.

At the molecular level, glucocorticoids stimulate the differentiation of preadipocytes into mature adipocytes and enhance lipoprotein lipase activity in peripheral fat tissues [6], thereby increasing the uptake of circulating fatty acids and the storage of triglycerides. At the same time, they increase hepatic lipogenesis and modulate cortisol receptor homeostasis (e.g., 11β-HSD1 in adipose tissue), favoring visceral fat distribution [6]. Although glucocorticoids can induce acute lipolysis, they exert chronic lipogenic effects – especially in subcutaneous adipose tissue – which promotes fat accumulation in the face, neck, and trunk [6]. This central adiposity, characteristic of CS, is further enhanced by increased hepatic lipogenesis and the overexpression of 11β-HSD1 in adipose tissue, which amplifies the local action of cortisol [6].

Case Presentation

In 2019, a 16-year-old female patient was initially diagnosed with a 4 × 3 mm pituitary microadenoma (Figure 1), following clinical suspicion of Cushing’s disease. The diagnosis was confirmed through imaging studies and endocrinological testing, which revealed consistently elevated urinary free cortisol levels ranging from 459 to 740.07 µg/24 hours (normal range: <50 µg/24 hours), indicative of endogenous hypercortisolism. No dynamic load tests (such as dexamethasone suppression or ACTH stimulation) were performed, as the diagnosis was supported by the clinical context and laboratory findings. Moreover, no clinical or biochemical evidence of adrenal insufficiency was observed during follow-up.

T1-weighted-sagittal-MRI-scan-showing-a-corticotroph-pituitary-microadenoma-(4-×-3-mm)-circled-in-red
Figure 1: T1-weighted sagittal MRI scan showing a corticotroph pituitary microadenoma (4 × 3 mm) circled in red

The lesion is localized within the anterior pituitary gland, consistent with an ACTH-secreting adenoma causing Cushing’s disease in the patient.

MRI, magnetic resonance imaging; ACTH, adrenocorticotropic hormone

The patient underwent transsphenoidal endonasal resection of the pituitary tumor in 2019. Although initially successful, disease recurrence was confirmed, and a second endonasal transsphenoidal surgery was performed in 2024. Despite these interventions, the prolonged hypercortisolism led to the development of secondary lipodystrophy, manifesting as centripetal fat accumulation, a dorsal fat pad, and disproportionate truncal adiposity (Figure 2). These physical alterations had a significant psychosocial impact, as reported by the patient during follow-up visits, resulting in body image dissatisfaction, low self-esteem, and social withdrawal. No formal psychometric scales were administered.

Preoperative-and-intraoperative-images-of-the-patient
Figure 2: Preoperative and intraoperative images of the patient

A and B panels show the anterior and posterior views prior to liposuction, demonstrating centripetal adipose accumulation characteristic of Cushing’s syndrome. The C panel shows the intraoperative stage following abdominal and flank liposuction, with placement of drainage tubes, and visible reduction in subcutaneous fat volume.

A thyroid function panel revealed a slightly elevated thyroid-stimulating hormone (TSH) level (4.280 μUI/mL; reference range: 0.270-4.200), with total and free T3 and T4 values within normal limits, ruling out clinically significant hypothyroidism as a confounding factor for her phenotype. The biochemical profile suggested a euthyroid state, despite borderline TSH elevation, which was interpreted as a subclinical or adaptive response to chronic cortisol excess (Table 1).

Parameter Normal Range Patient’s Value
Cortisol (µg/24 hour) 58.0 – 403.0 459.5 – 740.07
TSH (µUI/mL) 0.270 – 4.200 4.280
Total T3 (ng/mL) 0.80 – 2.00 1.02
Free T3 (pg/mL) 2.00 – 4.40 3.33
Total T4 (µg/dL) 4.50 – 12.00 8.63
Free T4 (ng/dL) 0.92 – 1.68 1.36
Table 1: Comparison between the patient’s hormone levels and standard reference ranges

A persistently elevated 24-hour urinary cortisol range is observed, consistent with endogenous hypercortisolism. The thyroid profile remains within normal limits, with a mildly elevated TSH in the absence of overt thyroid dysfunction. These findings support the functional and metabolic profile characteristic of Cushing’s syndrome.

TSH, thyroid-stimulating hormone

The procedure targeted lipodystrophic regions identified through clinical examination and patient concerns, rather than formal imaging or anthropometric measurements. It aimed to restore body contour, alleviate somatic distress, and improve her overall self-perception and quality of life. Postoperative follow-up revealed patient-reported improvements in body image and psychological well-being. While these outcomes were not evaluated with formal instruments, the clinical improvement was evident and significant from the patient’s perspective, highlighting the role of plastic surgery not only as a reconstructive tool, but also as a therapeutic strategy for restoring dignity and social functioning in patients recovering from CS.

Discussion

After successful treatment of the pituitary adenoma, many metabolic parameters improve; however, fat distribution usually only partially reverses. Longitudinal studies show that, in the medium term, weight and abdominal circumference decrease, and there is some redistribution of fat toward the limbs following cortisol remission [3].

For example, Bavaresco et al. (2024) observed that, after hormone levels normalized, total fat was reduced and part of it shifted from the visceral area to the legs [3]. Nevertheless, their review highlights that a significant proportion of patients continue to present with residual visceral adiposity and moderate obesity (body mass index, or BMI >25), despite hormonal control [7]. In our case, truncal adiposity persisted based on clinical assessment, though no formal anthropometric measurements were performed.

Although liposuction is not traditionally considered first-line therapy for cortisol-induced lipodystrophy secondary to Cushing’s disease, increasing evidence from related lipodystrophic syndromes supports its clinical utility. For instance, in human immunodeficiency virus (HIV)-associated cervicodorsal lipodystrophy, Barton et al. (2021) conducted a 15-year retrospective analysis comparing liposuction and excisional lipectomy, finding that 80% of patients undergoing liposuction alone experienced recurrence, while none of the patients treated with excisional lipectomy showed recurrence – albeit with a higher risk of postoperative seroma formation [7]. These findings underscore that, while liposuction may be less durable than excision, it remains a viable option for selected cases, especially when used for contouring or as an adjunct [7]. Similarly, the Endocrine Society guidelines on lipodystrophy management emphasize the importance of personalized approaches, particularly when localized adipose accumulation contributes to persistent metabolic dysfunction or psychological distress [8]. Akinci et al. (2024) also highlight that, even in partial or atypical lipodystrophy syndromes, patients often report substantial impairment in quality of life due to disfiguring fat redistribution [9]. In this context, liposuction should not be dismissed as merely cosmetic but considered part of a functional and psychosocial rehabilitation strategy. The present case exemplifies this rationale, as the patient – despite biochemical remission of Cushing’s disease – continued to experience debilitating body image disturbances and emotional distress, which were ameliorated following targeted liposuction. This supports the integration of body-contouring procedures into multidisciplinary care protocols for endocrine-related lipodystrophies, especially when residual physical stigma persists after hormonal normalization [7-9].

Body image disorders, such as those secondary to CS or lipodystrophy, significantly impact self-perception, self-esteem, and social functioning. For example, a study by Alcalar et al. (2013) reported that patients with active Cushing’s disease had significantly lower SF-36 scores – particularly in emotional role functioning and mental health domains – compared to controls [10]. Similarly, Akinci et al. (2024) described that patients with partial lipodystrophy demonstrated marked reductions in EQ-5D index values and visual analog scale (VAS) scores, indicating impaired health-related quality of life [9]. These findings underscore that fat redistribution disorders can substantially compromise psychosocial well-being, even after endocrine remission.

This is especially relevant in women, where sociocultural stereotypes surrounding female physical appearance reinforce thinness, symmetry, and youthfulness as standards of personal value and social acceptance [1]. This societal context amplifies body dissatisfaction when visible physical changes occur, even after the clinical remission of endocrine diseases, often leading to social withdrawal, anxiety, or depression [3,10]. Within this framework, plastic surgery – such as reconstructive liposuction – has proven to be a valuable therapeutic tool, offering physical restoration that can enhance self-confidence and promote social reintegration [4]. Postoperative follow-up in our case revealed patient-reported improvements in body image and psychological well-being. While these outcomes were not assessed using formal psychometric tools, the clinical benefit was evident from the patient’s perspective. This aligns with prior findings demonstrating the psychosocial value of reconstructive surgery, which can enhance self-esteem and social reintegration after physical disfigurement [11,12]. These observations underscore the role of plastic surgery not only as a reconstructive intervention, but also as a therapeutic strategy for restoring dignity and quality of life in patients recovering from CS.

Although validated psychometric instruments such as the Body Image Quality of Life Inventory (BIQLI) and the Dysmorphic Concern Questionnaire (DCQ) are available to assess body image disturbances, these were not applied in our case. Nonetheless, they represent useful tools for evaluating subjective impact in both clinical practice and research settings. The BIQLI evaluates the effect of body image on various aspects of life – social interactions, self-worth, sexuality, and emotional well-being – using a Likert scale ranging from -3 (very negative impact) to +3 (very positive impact), providing a quantifiable assessment of its influence on quality of life [5]. The DCQ, on the other hand, identifies dysfunctional concerns about perceived physical flaws by assessing behaviors such as avoidance, mirror checking, and concealment; higher scores are associated with suspected body dysmorphic disorder (BDD) [6]. These tools are useful for initial diagnosis, surgical candidate selection, and postoperative follow-up, as they objectively measure subjective changes related to body image. Their advantages include ease of use, clinical validity, and applicability in research settings. However, they also have limitations: they do not replace comprehensive psychological evaluation, may be influenced by cultural context, and do not detect deeper psychiatric comorbidities. Therefore, a multidisciplinary and ethically grounded approach – integrating plastic surgery, endocrinology, and psychology – is essential to ensure safe and patient-centered treatment planning.

Aesthetic liposuction is associated with significant improvements in perceived body image and patient quality of life [11]. For example, Papadopulos et al. (2019) observed statistically significant increases in perception of one’s own body appearance and high satisfaction with postoperative results [12]. These aesthetic gains were accompanied by psychological improvements: the same study documented an increase in emotional stability and a reduction in postoperative anxiety [12]. Similarly, Kamundi (2023) found that nearly all assessed dimensions of quality of life improved after liposuction (p < 0.05 in most of them). Altogether, these findings suggest that liposuction not only corrects physical alterations typical of CS, but also strengthens self-esteem and psychological well-being by substantially improving satisfaction with one’s body image [11].

Moreover, self-esteem influences adherence to medical treatments and lifestyle changes. By improving self-image through reconstructive surgery, it is plausible that the patient feels more motivated to maintain healthy habits, such as diet and regular exercise, that prevent metabolic relapse [12,13].

Nonetheless, it is important to emphasize that liposuction, in this context, should be viewed as a reconstructive complement, not a primary treatment. There are no established protocols or formal guidelines that explicitly include plastic surgery in the care of cured CS; the decision is personalized, based on the residual functional and psychological impact.

Conclusions

Reconstructive plastic surgery, though not a primary therapeutic approach for CS, plays a key role in enhancing patients’ quality of life following remission. Liposuction, in particular, offers a safe and effective solution for persistent lipodystrophy, providing aesthetic benefits with minimal scarring, rapid recovery, and low complication rates in properly selected patients.

This case underscores the importance of addressing both physical and psychosocial sequelae after endocrine stabilization. A multidisciplinary approach – encompassing endocrinology, neurosurgery, and plastic surgery – not only restores physical appearance but also contributes to emotional recovery, self-esteem, and overall patient satisfaction.

References

  1. Tatsi 😄 Cushing syndrome/disease in children and adolescents. Endotext [Internet]. Feingold KR, Ahmed SF, Anawalt B, et al. (ed): MDText.com, Inc., South Dartmouth (MA); 2000.
  2. Mir N, Chin SA, Riddell MC, Beaudry JL: Genomic and non-genomic actions of glucocorticoids on adipose tissue lipid metabolism. Int J Mol Sci. 2021, 22:8503. 10.3390/ijms22168503
  3. Bavaresco A, Mazzeo P, Lazzara M, Barbot M: Adipose tissue in cortisol excess: what Cushing’s syndrome can teach us?. Biochem Pharmacol. 2024, 223:116137. 10.1016/j.bcp.2024.116137
  4. Nieman LK: Molecular derangements and the diagnosis of ACTH-dependent Cushing’s syndrome. Endocr Rev. 2022, 43:852-77. 10.1210/endrev/bnab046
  5. Patni N, Chard C, Araujo-Vilar D, Phillips H, Magee DA, Akinci B: Diagnosis, treatment and management of lipodystrophy: the physician perspective on the patient journey. Orphanet J Rare Dis. 2024, 19:263. 10.1186/s13023-024-03245-3
  6. Peckett AJ, Wright DC, Riddell MC: The effects of glucocorticoids on adipose tissue lipid metabolism. Metabolism. 2011, 60:1500-10. 10.1016/j.metabol.2011.06.012
  7. Barton N, Moore R, Prasad K, Evans G: Excisional lipectomy versus liposuction in HIV-associated lipodystrophy. Arch Plast Surg. 2021, 48:685-90. 10.5999/aps.2020.02285
  8. Brown RJ, Araujo-Vilar D, Cheung PT, et al.: The diagnosis and management of lipodystrophy syndromes: a multi-society practice guideline. J Clin Endocrinol Metab. 2016, 101:4500-11. 10.1210/jc.2016-2466
  9. Akinci B, Celik Gular M, Oral EA: Lipodystrophy syndromes: presentation and treatment. Endotext [Internet]. Feingold KR, Anawalt B, Boyce A, et al. (ed): MDText.com, Inc., South Dartmouth (MA); 2024.
  10. Alcalar N, Ozkan S, Kadioglu P, Celik O, Cagatay P, Kucukyuruk B, Gazioglu N: Evaluation of depression, quality of life and body image in patients with Cushing’s disease. Pituitary. 2013, 16:333-40. 10.1007/s11102-012-0425-5
  11. Kamundi RK: Determining the Impact of Liposuction on Patient Satisfaction of Quality of Life and Body Image: A Prospective Study in Nairobi, Kenya. University of Nairobi, Nairobi; 2023.
  12. Papadopulos NA, Kolassa MJ, Henrich G, Herschbach P, Kovacs L, Machens HG, Klöppel M: Quality of life following aesthetic liposuction: a prospective outcome study. J Plast Reconstr Aesthet Surg. 2019, 72:1363-72. 10.1016/j.bjps.2019.04.008
  13. Saariniemi KM, Salmi AM, Peltoniemi HH, Charpentier P, Kuokkanen HOM: Does liposuction improve body image and symptoms of eating disorders?. Plast Reconstr Surg Glob Open. 2015, 3:461. 10.1097/GOX.0000000000000440

From https://www.cureus.com/articles/376886-reconstructive-liposuction-for-residual-lipodystrophy-after-remission-of-cushings-disease-a-case-report#!/

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Double Synchronous Functional Pituitary Adenomas Causing Acromegaly and Subclinical Cushing Disease

Posted on July 1, 2025 by MaryO

Abstract

Double pituitary adenomas with growth hormone (GH) and adrenocorticotropic hormone (ACTH) secretion are very rare. They are responsible for acromegaly with hypercortisolism. Subclinical corticotropic adenomas are exceptional.
Herein, we report the case of a patient with double functional pituitary adenomas causing acromegaly and subclinical Cushing’s disease. A 45-year-old woman was referred to our Department for suspected acromegaly. Her past medical history included diabetes mellitus treated with oral antidiabetic drugs and hypertension.
On physical examination, she had a large prominent forehead, thickened lips, increased interdental spacing, prognathism, and enlarged hands and feet. No signs of hypercortisolism were found. Biological investigations showed an elevated insulin growth factor-1 (IGF-1) level at 555 ng/mL, a GH nadir after 75 g oral glucose tolerance test at 2 ng/mL, a morning cortisol level at 158 ng/mL, an ACTH level at 64 pg/mL, a thyroid stimulating hormone (TSH) level at 2.26 mIU/L, and a free thyroxine (FT4) level at 12.8 pmol/L. Cortisol level after low-dose dexamethasone suppression test was 86 ng/mL.
The diagnosis of acromegaly associated with Cushing’s disease was established. Pituitary magnetic resonance imaging showed a pituitary macroadenoma with no clear limits. The patient underwent transsphenoidal tumor resection. The pathological examination revealed two separate pituitary adenomas. The positivity to ACTH and GH was 100% and 80%, respectively.
This case emphasizes the necessity of an evaluation of all the pituitary axes in case of adenoma in order not to miss a double hormonal secretion or more even in the absence of suggestive clinical signs.

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Personalized Noninvasive Diagnostic Algorithms Based on Urinary Free Cortisol in ACTH-dependant Cushing’s Syndrome

Posted on November 9, 2024 by MaryO

Julie Lavoillotte, Kamel Mohammedi, Sylvie Salenave, Raluca Maria Furnica, Dominique Maiter, Philippe Chanson, Jacques Young, Antoine Tabarin
The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 11, November 2024, Pages 2882–2891
https://doi.org/10.1210/clinem/dgae258

Abstract

Context

Current guidelines for distinguishing Cushing’s disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary magnetic resonance imaging (MRI) as first-line investigation for all patients. CRH testing is no longer available, and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients.

Objective

To establish noninvasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters.

Design

Retrospective study.

Setting

University hospitals.

Patients

Two hundred forty-seven CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served as external validation.

Results

Twenty-four-hour urinary free cortisol (UFC) had the highest area under the receiver operating characteristic curve for discrimination of CD from EAS (.96 [95% confidence interval (CI), .92–.99] in the primary study and .99 [95% CI, .98–1.00] in the validation cohort). The addition of clinical, imaging, and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (C-statistic index .99 [95% CI, .97–1.00]). Three groups were defined based on baseline UFC: < 3 (group 1), 3–10 (group 2), and > 10 × the upper limit of normal (group 3), and they were associated with 0%, 6.1%, and 66.7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group 1, MRI first followed by neck-to-pelvis computed tomography scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value.

Conclusion

UFC accurately predicts EAS and can serve to define personalized and noninvasive diagnostic algorithms.

Read the article here: https://academic.oup.com/jcem/article/109/11/2882/7645065

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