Treatment-Resistant Cushing Disease and Acromegaly in a Young Woman: A Case Of Functional Pituitary Macroadenoma

Posted on March 14, 2025 by MaryO

Abstract

Cushing disease and acromegaly are common endocrine disorders caused by excessive cortisol and growth hormone production, respectively. Both conditions can co-occur due to functioning pituitary adenomas, which are typically benign pituitary gland tumors. This report discusses a 30-year-old woman with hyperpituitarism leading to treatment-resistant Cushing disease and acromegaly caused by a functional pituitary macroadenoma.
A 30-year-old woman presented with a history of excessive weight gain, facial puffiness, fatigue, persistent headaches, and visual disturbances. Clinical examination revealed features consistent with Cushing disease and acromegaly, including a moon face, central obesity, and large hands and feet—the ophthalmologic evaluation identified bitemporal hemianopia, suggesting optic chiasm compression. Laboratory results showed elevated ACTH, IGF-1, and prolactin levels, alongside confirmed hypercortisolism. The patient also had secondary diabetes mellitus and galactorrhea—initial treatment with octreotide provided limited benefit, with persistent hormone elevations and insufficient symptom control. The patient underwent endonasal endoscopic transsphenoidal resection of the pituitary macroadenoma, leading to marked symptomatic and hormonal improvements. This underscores the diagnostic challenge and treatment complexity of such cases. Early diagnosis is critical for optimizing outcomes in patients with hyperpituitarism and mitigating complications. This case highlights the importance of multidisciplinary management and the necessity of long-term follow-up to monitor for recurrence and ensure sustained remission.

Introduction

Pituitary adenomas are benign tumors arising from the pituitary gland, often referred to as the “master gland” due to its central role in regulating key physiological processes such as growth, metabolism, and reproduction [1,2]. These tumors are classified by size into microadenomas (<10 mm) and macroadenomas (≥10 mm) and by hormonal activity into functioning and nonfunctioning adenomas. Functioning adenomas actively secrete hormones, leading to distinct syndromes such as prolactinomas, acromegaly (from growth hormone overproduction), and Cushing disease (from excess ACTH). In contrast, nonfunctioning adenomas do not secrete hormones but may cause symptoms due to mass effects, such as visual disturbances or hypopituitarism [[3], [4], [5]].
The simultaneous occurrence of Cushing disease and acromegaly is rare and presents a significant diagnostic and therapeutic challenge. Both conditions stem from hyperpituitarism, typically due to a functional pituitary adenoma [6,7]. Cushing disease results from ACTH hypersecretion, causing excessive cortisol production and features such as central obesity, hypertension, hyperglycemia, and muscle weakness [[8], [9], [10]]. Prolonged cortisol exposure can lead to severe complications, including cardiovascular diseases and osteoporosis. Acromegaly, on the other hand, arises from growth hormone overproduction, leading to elevated IGF-1 levels and characteristic features such as enlarged extremities, facial changes, and systemic complications like insulin resistance and joint abnormalities [[11], [12], [13]].
The coexistence of Cushing disease and acromegaly within the same affected person is extraordinarily rare, making this particular case record particularly noteworthy [14,15].
The simultaneous presentation of these 2 endocrine problems in a young lady because of a hormonally functioning pituitary macroadenoma presents a unique scientific venture [16,17]. The pituitary macroadenoma, defined as a tumor more than 10 mm in diameter, can compress adjoining structures within the sella turcica and enlarge into surrounding areas, leading to signs and symptoms with complications, visible disturbances, and hyperpituitarism. In this case, the patient presented with both Cushing disease and acromegaly, at the same time symptoms as a result of the mass impact of the macroadenoma.
The case of a 30-year-old female with hyperpituitarism, characterized with the aid of drug-resistant Cushing disease and acromegaly, highlights the complexities intricately associated with the analysis and control of a couple of endocrine issues bobbing up from a single pituitary macroadenoma. Her medical presentation changed into one marked by a history of noticeable weight gain, facial puffiness, fatigue, chronic complications, and visual disturbances. A thorough physical exam found traits consistent with each Cushing disorder and acromegaly, which include a moon face, vital weight problems, and enlarged arms and toes. The ophthalmologic exam confirmed bitemporal hemianopia, indicative of optic chiasm compression with the aid of the pituitary macroadenoma. Early recognition and multidisciplinary management are essential to mitigate the significant morbidity associated with these conditions. This case report highlights a rare instance of concurrent Cushing disease and acromegaly due to a functional pituitary macroadenoma, underscoring the importance of timely diagnosis and treatment.

Case presentation

This case of a 30-year-old female highlights the complexities of diagnosing and managing a functional pituitary macroadenoma presenting with overlapping features of Cushing disease and acromegaly, along with secondary diabetes mellitus.
The patient demonstrated classic signs of hypercortisolism, including central obesity with a “moon face” and “buffalo hump,” skin thinning, easy bruising, and muscle weakness. Cortisol’s catabolic effects were evident in her limb wasting and truncal obesity. Metabolic complications included hypertension and secondary diabetes mellitus, supported by elevated random blood sugar (22 mmol/L) and postprandial blood sugar levels (27 mmol/L). Laboratory findings showed significantly elevated ACTH levels (670 pg/mL; normal: 10–60 pg/mL) and increased morning urine cortisol levels.
The patient also exhibited hallmark features of acromegaly, including enlarged hands and feet, necessitating larger shoe and glove sizes, and distinct facial changes such as mandibular prognathism, frontal bossing, and nasal broadening. Soft tissue swelling and fatigue were also noted, alongside joint pain likely resulting from cartilage and bone overgrowth. Her IGF-1 levels were markedly elevated (798 ng/mL; normal: 100–300 ng/mL).
Hyperprolactinemia (643 ng/mL; normal: 5–25 ng/mL) caused galactorrhea, likely resulting from tumor compression of the pituitary stalk or direct prolactin secretion. Diabetes mellitus, secondary to insulin resistance driven by excess cortisol and growth hormone, further complicated her clinical picture (Table 1).

Table 1. Markedly elevated hormone levels preoperatively and their postoperative normalization.

Hormone Patient’s level (Preoperative) Postoperative levels Normal reference value
ACTH 670 pg/mL 90 pg/mL 10–60 pg/mL
IGF-1 798 ng/mL 280 ng/mL 100–300 ng/mL (age-dependent)
Prolactin 643 ng/mL 42 ng/mL 5–25 ng/mL
Morning Urine Cortisol Elevated Normal <50 mcg/24 h
Random Blood Sugar 22 mmol/L 6.5 mmol/L 4.0–7.8 mmol/L
2-Hour Postprandial Blood Sugar 27 mmol/L 7.0 mmol/L <7.8 mmol/L
TSH (Thyroid-Stimulating Hormone) 0.8 mIU/L 1.2 mIU/L 0.5–5.0 mIU/L
FT3 (Free Triiodothyronine) 4.5 pmol/L 4.0 pmol/L 3.5–7.7 pmol/L
FT4 (Free Thyroxine) 15 pmol/L 16 pmol/L 12–22 pmol/L
Secondary diabetes mellitus is a common trouble in sufferers with Cushing disease and acromegaly, stemming from the insulin resistance brought about by persistent hypercortisolism and hypersecretion of GH. This patient’s multiplied blood sugar also reflects tremendous impairment in glucose metabolism. Polyuria, polydipsia, and unexplained weight loss are classic signs of diabetes that could have been found in her clinical history but are frequently overshadowed by the traits of the more distinguished functions of her endocrine disorders. The affected person additionally experienced galactorrhea, an odd milk discharge from the breasts, that’s on account of her expanded prolactin levels (643 ng/mL, ordinary range: 2-29 ng/mL). Hyperprolactinemia inside the context of a pituitary macroadenoma can result from the tumor’s direct secretion of prolactin or from the stalk effect, where the tumor compresses the pituitary stalk, disrupting dopamine inhibition of prolactin secretion.
MRI was the primary imaging modality, revealing a large pituitary macroadenoma centered within the sella turcica and extending suprasellar. The tumor demonstrated homogeneous postcontrast enhancement and exerted mass effects, including optic chiasm compression correlating with bitemporal hemianopia. Other modalities, such as CT, were not considered due to MRI’s superior resolution for pituitary evaluation.
The MRI scans of the patient reveal a large, well-defined pituitary macroadenoma centered within the sella turcica, exhibiting significant suprasellar extension. On sagittal T1-weighted postcontrast imaging (Fig. 1), the lesion demonstrates homogeneous enhancement with clear, well-defined borders, expanding superiorly into the suprasellar region. Coronal T2-weighted images (Fig. 2) further delineate this suprasellar extension, with the mass exerting mass effect on adjacent structures.
Fig 1:

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Fig. 1. This sagittal T1-weighted postcontrast MRI of the brain, specifically focusing on the sella turcica region, reveals a large, homogeneously enhancing mass centered within the sella turcica, consistent with a pituitary macroadenoma. The mass exhibits clear, well-defined borders and appears to expand the sella, with extension into the suprasellar region (marked by circle).

Fig 2:

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Fig. 2. This image shows MRI scan of the brain in coronal T2-weighted images which reveals large suprasellar mass (marked by circles).

Additional sagittal T1-weighted postcontrast imaging (Fig. 3) confirms the uniform enhancement of the macroadenoma, filling the sella turcica and extending upward. Coronal T2-weighted MRI (Fig. 4) reveals the lesion as hyperintense, extending into the suprasellar region and displacing the optic chiasm. The imaging highlights the well-defined borders of the mass and the potential mass effect on adjacent structures.
Fig 3:

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Fig. 3. Sagittal T1-weighted postcontrast MRI depicting a large, homogeneously enhancing pituitary macroadenoma within the sella turcica, expanding into the suprasellar region with well-defined borders (marked by arrows).

Fig 4:

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Fig. 4. Coronal T2-weighted MRI demonstrating a large, hyperintense pituitary macroadenoma within the sella turcica, extending into the suprasellar region (marked by arrows). The lesion displaces the optic chiasm and exhibits well-defined borders, suggesting potential mass effect.

Axial T2-weighted MRI images (Fig. 5) depict a hyperintense lesion in the basal ganglia and thalamus, appearing as a bright, well-defined signal. This finding suggests a potential coexisting pathology affecting deep brain structures, which may or may not be related to the primary pituitary lesion. The characteristics and location of the pituitary macroadenoma correspond with the patient’s clinical presentation of bitemporal hemianopia, likely caused by compression of the optic chiasm.
Fig 5:

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Fig. 5. Axial T2-weighted MRI images of the brain showing a hyperintense lesion in the region of the basal ganglia and thalamus, indicated by white arrows. The lesion appears as a well-defined, bright signal, suggestive of a pathology affecting deep brain structure.

The overall imaging features, including homogeneous enhancement, well-defined borders, and suprasellar extension, are hallmark characteristics of pituitary macroadenomas. The potential lateral extension toward the cavernous sinus warrants further evaluation, while the hyperintense lesion in the basal ganglia and thalamus may indicate secondary effects or unrelated CNS pathology.
The imaging findings collectively support the diagnosis of a large, functioning pituitary macroadenoma, exceeding 10 mm in diameter. The mass’s size and anatomical impact align with the patient’s clinical presentation, which includes headaches, visual field deficits, and hormonal imbalances. The documented compression of the optic chiasm and possible involvement of the cavernous sinus provide a radiological explanation for the patient’s visual symptoms and hormonal disruptions. This MRI assessment substantiates the diagnosis of a pituitary macroadenoma with significant suprasellar extension and compression effects, consistent with the patient’s symptomatology and clinical findings.
The conglomeration of her clinical presentations, elevated hormone levels, and MRI findings of a big suprasellar mass pretty suggestive of a pituitary macroadenoma showed the analysis of a functioning pituitary adenoma. The preliminary treatment control with octreotide, a somatostatin analog, aimed to control both acromegaly and Cushing disorder by inhibiting GH and ACTH secretion. However, the suboptimal reaction highlighted the undertaking of achieving hormone manipulation in sufferers with massive, competitive adenomas.
Given the patient’s persistent symptoms and the insufficient biochemical response to medical therapy, surgical intervention was considered imperative. The patient underwent endonasal endoscopic transsphenoidal resection of the pituitary gland, a minimally invasive surgical approach targeting the tumor via the nasal passages. This approach was preferred over traditional craniotomy due to its demonstrated efficacy in reducing tumor size and lowering elevated hormone levels with fewer complications, reduced morbidity, shorter hospital stays, and faster recovery times. Additionally, the endoscopic technique offers superior visualization of the surgical field, which aids in precise tumor resection and preservation of normal pituitary tissue.
During the surgery, the tumor was noted to be soft and well-circumscribed, with no significant adherence to adjacent structures such as the cavernous sinus or optic chiasm. This facilitated a complete resection of the tumor, minimizing the risk of residual disease. There were no notable intraoperative complications, such as cerebrospinal fluid leakage or significant bleeding, underscoring the safety and efficacy of the chosen approach. Postoperatively, the patient demonstrated marked clinical improvement in her symptoms, accompanied by a significant reduction in hormone levels to within normal reference ranges. This confirmed the diagnosis and highlighted the effectiveness of the surgical intervention. Specifically, there was a substantial decrease in ACTH, IGF-1, and prolactin levels, leading to clinical remission of Cushing disease and acromegaly.
In the postoperative period, the patient did not require immediate hormone replacement therapy, as her endocrine functions remained stable. However, long-term monitoring is planned to assess for potential hormone deficiencies, disease recurrence, or other complications. The follow-up plan includes regular clinical evaluations, hormonal assays, and periodic imaging studies to ensure sustained remission and to promptly address any residual or recurrent tumor growth. This case highlights the crucial role of surgical intervention in managing functional pituitary macroadenomas, particularly when medical therapy fails. The successful outcome underscores the importance of a multidisciplinary approach and the need for lifelong surveillance to optimize long-term outcomes for such patients. This case scenario also underscores the complexities interwoven in diagnosing and coping with hyperpituitarism because of a pituitary macroadenoma, emphasizing the warrant for a complete and multidisciplinary approach. Early recognition of symptoms, correct diagnostic workup, and timely endocrine disorders.

Discussion

The case of this 30-year-old woman with concurrent refractory Cushing disease and acromegaly due to a functional pituitary macroadenoma highlights the challenges inherent in diagnosing and managing multiple endocrine disorders. Recognizing overlapping clinical features was central to reaching the diagnosis. Classic symptoms of Cushing disease, such as a moon face and central obesity, coupled with acromegalic features, including enlarged extremities, underscored the complexity of the case. The presence of bitemporal hemianopia further pointed to a large pituitary mass compressing the optic chiasm, necessitating imaging studies for confirmation. This case underscores the need for clinicians to remain vigilant when evaluating overlapping endocrine features to avoid delays in diagnosis and treatment [[18], [19], [20]].
Laboratory evaluations were pivotal, revealing markedly elevated ACTH, IGF-1, and prolactin levels, in addition to evidence of hypercortisolism and secondary diabetes mellitus. These findings highlighted the intricate interplay of hypersecreted pituitary hormones and the systemic consequences of unregulated hormone production. MRI findings of a large suprasellar pituitary tumor were instrumental in confirming the diagnosis of a functional macroadenoma and guided subsequent treatment decisions.
The patient’s suboptimal response to octreotide therapy underscored the limitations of medical treatments in addressing aggressive, hormone-secreting pituitary macroadenomas. While somatostatin analogs are effective in many cases of acromegaly and can provide symptomatic relief, their efficacy is limited in patients with large adenomas and significant hormonal hypersecretion. This case highlights the necessity of early consideration of definitive surgical intervention when medical therapy fails to achieve adequate biochemical control [[21], [22], [23]].
Endonasal endoscopic transsphenoidal surgery was selected for this patient due to its minimally invasive approach, superior visualization of the sellar region, and lower complication rates compared to traditional craniotomy. Intraoperatively, the tumor’s soft consistency and lack of adherence to adjacent structures facilitated a complete resection. Notably, the absence of significant complications, such as cerebrospinal fluid leakage or vascular injury, reflected the safety and precision of this surgical approach [[24], [25], [26]].
Postoperatively, the patient experienced substantial improvement in symptoms, with normalization of ACTH, IGF-1, and prolactin levels. This outcome underscores the efficacy of surgical intervention in achieving hormonal remission and alleviating symptoms in patients with functional macroadenomas. The resolution of her secondary diabetes mellitus and galactorrhea further reinforced the success of treatment [[27], [28], [29]].
Managing such complex endocrine disorders necessitates a multidisciplinary approach, with endocrinologists, radiologists, and neurosurgeons collaborating to ensure accurate diagnosis and effective treatment planning. Radiologists play a critical role in identifying and characterizing pituitary tumors, while endocrinologists monitor hormonal responses and guide perioperative management [[30], [31], [32]]. Neurosurgeons provide expertise in resecting these challenging lesions and optimizing patient outcomes.
The prognosis for patients undergoing surgical resection of functional pituitary macroadenomas is generally favorable when hormonal remission is achieved. However, long-term follow-up is critical to monitor for potential disease recurrence and manage any residual hormone deficiencies. Lifelong surveillance, including periodic hormonal assays and imaging studies, is recommended. Although the patient did not require immediate hormone replacement therapy, ongoing assessment of endocrine function remains essential to address emerging deficiencies promptly [[33], [34], [35], [36]].
This case exemplifies the importance of integrating current evidence-based practices into patient care. Recent guidelines and studies emphasize the role of endoscopic surgery as the preferred approach for resecting pituitary tumors due to its high success rates and reduced morbidity compared to older techniques.

Conclusion

This case highlights the pivotal role of surgical intervention in managing hormone-resistant pituitary macroadenomas underscoring the role of a multidisciplinary approach involving endocrinology, radiology, and neurosurgery, demonstrating its effectiveness in resolving hormonal overproduction and alleviating symptoms. Long-term follow-up is indispensable to monitor for recurrence, address emerging complications, and ensure sustained remission, reinforcing the need for vigilance and specialized endocrine care in managing these complex disorders.

Patient consent

Written informed consent for publication of this case report was obtained from the patient(s). The patient(s) were provided with sufficient information regarding the nature of the publication, including the details to be disclosed and potential implications. The patient(s) have confirmed their understanding and voluntarily agreed to the publication of this case report.

References

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Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Avascular Necrosis in Patients With Cushing Syndrome

Posted on March 12, 2025 by MaryO

Abstract

Cushing syndrome (CS) results from prolonged exposure to excess glucocorticoids, leading to a range of clinical manifestations including avascular necrosis (AVN), a rare complication of CS. Although AVN is often associated with exogenous glucocorticoid treatment, it can occur in endogenous CS but may be unrecognized because of its rarity and possibly from a subclinical presentation. We describe a case of a 71-year-old male with florid Cushing disease who initially presented with bilateral hip AVN and later developed bilateral shoulder AVN despite achieving biochemical remission following transsphenoidal surgery and adjuvant stereotactic photon radiosurgery. AVN in endogenous CS is underreported, and guidance on routine screening is lacking. Our case underscores the importance of considering AVN in patients with CS, especially in those with persistent or recurrent joint symptoms and markedly elevated cortisol levels. Early detection of AVN is crucial as it can lead to irreversible joint damage and disability if untreated. Screening strategies should be explored to identify high-risk patients who are diagnosed with CS for timely intervention, thereby preventing long-term morbidity associated with AVN.

Introduction

Cushing syndrome (CS) results from prolonged exposure to excess glucocorticoids, either from exogenous glucocorticoids or endogenous sources. In endogenous CS, hypercortisolism may be due to an ACTH-dependent process, most often from a corticotroph adenoma in Cushing disease (CD) or from ectopic ACTH secretion from neuroendocrine tumors or other solid tumors such as small cell lung carcinoma. On the other hand, ACTH-independent CS is mainly driven from adrenal pathology including adrenal adenomas, adrenocortical carcinomas, adrenal hyperplasia, and primary pigmented micronodular disease [1]. The presenting symptoms and signs of CS include hypertension, diabetes mellitus, weight gain, facial plethora, dorsocervical fat pads, muscle weakness, and osteoporosis, most of which may be detected on physical examination or diagnosed biochemically. A less common symptom is avascular necrosis (AVN) of bone tissue [1, 2], which can present with pain or point tenderness of the hip or other joints as well as present subclinically [3].

AVN of the hip results from compromised blood supply to the bone tissue and usually impacts the hips and shoulders. This leads to necrosis of hematopoietic cells, adipocytes, and osteocytes. Subsequently, bone repair processes are activated, with differentiation of mesenchymal cells into osteoblasts to build new bone and hematopoietic stem cells into osteoclasts to remove necrotic tissue. However, because of impaired bone resorption and formation, subchondral fractures eventually occur [4]. Exogenous glucocorticoid treatment is 1 of the most common causes of AVN and may account for up to 38% of atraumatic AVN and is dose dependent [5]. Glucocorticoid treatment is theorized to cause AVN through increased systemic lipids, leading to compromised perfusion to the femoral head resulting from fat emboli or external lipocyte compression, as well as alterations in the inflammatory cytokines resulting in osteoclast activation and osteoblast apoptosis [4, 6]. Compared to exogenous glucocorticoid treatment, AVN caused by endogenous hypercortisolism is not frequently reported nor is it screened for on diagnosis of CS.

We describe a patient who presented with bilateral hip AVN in the context of florid CD. We aim to highlight this presenting feature to heighten awareness for screening for this progressive condition, which can potentially lead to joint damage, loss of mobility, and long-term disability.

Case Presentation

A 71-year-old male with medical history of active tobacco use and obstructive sleep apnea was diagnosed with new-onset hypertension during an annual health visit. He was started on antihypertensive medications (losartan, hydrochlorothiazide, and spironolactone) by his primary care doctor, but the hypertension remained uncontrolled. Over the course of 2 months, the patient developed progressive lower extremity edema and was started on furosemide, which led to hypokalemia and was subsequently discontinued. He clinically deteriorated, with progressive anasarca and dyspnea, and then developed acute left eye ptosis and diplopia and was admitted to the hospital. The patient also endorsed irritability, mood swings, easy bruising, low libido, increased appetite, 30-lb weight gain, and bilateral hip pain.

Diagnostic Assessment

Physical examination was significant for oral candidiasis, dorsocervical fat pad, facial plethora, proximal muscle weakness, and bilateral hip tenderness. Testing confirmed ACTH-dependent CS with elevated 24-hour urine free cortisol of 1116 μg/24 hours (30788.21 nmol/24 hours) and 1171.9 μg/24 hours (32330.38 nmol/24 hours) (normal reference range, 3.5-45 μg/24 hours; 96.56-1241.46 nmol/24 hours) and ACTH of 173 pg/mL (38.06 pmol/L) and 112 pg/mL (24.64 pmol/L) (normal reference range, 7.2-63 pg/mL; 1.58-13.86 pmol/L) on 2 separate occasions. He had hypogonadotropic hypogonadism with total testosterone levels of 41 ng/dL (1.42 nmol/L) (normal reference range, 250-1100 ng/dL; 8.68-38.17 nmol/mL) and suppressed LH and FSH at <0.2 mIU/mL (<0.2 IU/L) (normal reference range, 0.6-12.1; 0.6-12/1.1 IU/L) and 0.2 mIU/mL (<0.2 IU/L) (normal reference range, 1.0-12.0 2 mIU/mL; 1.0-12.0 2 IU/L) respectively, whereas the remaining pituitary hormones were normal, although IGF-1 was low normal at 66 ng/mL (8.65 nmol/L) (normal reference range, 7.2-63 pg/mL; 1.58-13.86 pmol/L). He also had new-onset diabetes mellitus with glycated hemoglobin of 8% (<5.7%) (Table 1). Imaging of the lungs showed a 15-mm solid noncalcified nodule in the posterior right upper lobe concerning for neoplasm. Pituitary magnetic resonance imaging (MRI) revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (Fig. 1). Additionally, pelvis computed tomography (CT) scan demonstrated bilateral avascular necrosis of the capital femoral epiphysis without evidence of fracture or subchondral collapse (Fig. 2A and 2B).

Pituitary magnetic resonance imaging (MRI) with gadolinium, using T1-weighted, turbo spin-echo revealed sequence revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (white arrow).

Figure 1.

Pituitary magnetic resonance imaging (MRI) with gadolinium, using T1-weighted, turbo spin-echo revealed sequence revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (white arrow).

Coronal inversion recovery image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (A). Axial proton density with fat saturation image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (B). Coronal T1 image of the right shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (C). Coronal T1 image of the left shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (D) (white arrows).

Figure 2.

Coronal inversion recovery image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (A). Axial proton density with fat saturation image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (B). Coronal T1 image of the right shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (C). Coronal T1 image of the left shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (D) (white arrows).

Table 1.

Laboratory evaluation of the patient at presentation

Lab Value Reference Range
Conventional units (Système International units)
ACTH 173 pg/mL (38.06 pmol/L) 7.2-63 pg/mL (1.58-13.86 pmol/L)
24-h urine free cortisol 1116 μg/24 h (30,788.21 nmol/24 h) 4.0-55.0 μg/24 h (110.35-1517.34 nmol/24 h)
Total testosterone 41 ng/mL (1.42 nmol/L) 250-1100 ng/mL (8.68-38.17 nmol/L)
Free testosterone 12.3 pg/mL (0.07 nmol/L) 30.0-135.0 pg/mL (0.17-0.79 nmol/L)
LH <0.2 mIU/mL (<0.2 IU/L) 0.6-12.1 mIU/mL (0.6-12.1 IU/L)
FSH 0.2 mIU/mL (0.2 IU/L) 1-12 mIU/mL (1-12 IU/L)
Prolactin 9.6 ng/mL (9.6 μg/L) 3.5-19.4 ng/mL (3.5-19.4 μg/L)
TSH 0.746 mIU/L 0.450-5.330 mIU/L
Free T4 0.66 ng/dL (8.49 pmol/L) 0.61-1.60 ng/dL (7.85-20.59 pmol/L
IGF-1
Z score		 66 ng/mL (8.65 nmol/L)
−0.9		 34-245 ng/mL (4.45-32.09 nmol/L)
−2.0 to +2.0
HbA1c 8.2% <5.7%

Abbreviations: Hb A1c, hemoglobin A1C.

Treatment

Prophylactic treatment was started with subcutaneous heparin for anticoagulation and trimethoprim-sulfamethoxazole for opportunistic infections. Orthopedic evaluation did not recommend acute intervention for the hip AVN. Given the pituitary macroadenoma on imaging and left cranial nerve VI palsy, it was determined that the patient likely had CD, so he underwent transsphenoidal surgery. Surgical pathology confirmed the adenoma was ACTH positive, sparsely granulated, with Ki-67 index of 4%, and without increased mitotic activity (Fig. 3).

Hematoxylin and eosin (A) and adrenocorticotropic hormone (B) stained sections show oval nuclei with “salt and pepper” chromatin and granular, ACTH-positive cytoplasm. Original magnification 250×.

Figure 3.

Hematoxylin and eosin (A) and adrenocorticotropic hormone (B) stained sections show oval nuclei with “salt and pepper” chromatin and granular, ACTH-positive cytoplasm. Original magnification 250×.

Outcome and Follow-up

Due to ongoing hypercortisolism (Table 2) and residual tumor in the left cavernous sinus, the patient underwent adjuvant treatment with stereotactic photon radiosurgery at a dose of 13 Gy targeted to the left cavernous sinus and was started on osilodrostat, an oral, reversible inhibitor of 11β-hydroxylase that drives the final step of cortisol synthesis and aldosterone synthase, which converts 11-deoxycorticosterone to aldosterone [7]. The starting dose of osilodrostat was 2 mg twice per day. As the patient developed nausea, lack of appetite, and malaise with decreasing cortisol levels, osilodrostat was reduced to 1 mg daily, and he was started on hydrocortisone replacement therapy on week 11 postoperatively (Table 3). Ultimately, both osilodrostat and hydrocortisone were discontinued following normalization of cortisol levels. Regarding the rest of the hormonal deficiencies, his total testosterone and IGF-1 levels improved to levels of 483 ng/dL (16.76 nmol/L) and 99 (12.97 nmol/L), respectively, and he did not require hormone replacement therapy. Clinically, the patient improved with resolution of his hypertension and diabetes and achieved a 38-lb weight loss. Additionally, his diplopia improved and his hip pain resolved without any restriction in mobility. However, 1 year postoperatively, the patient developed bilateral shoulder pain. MRI of the shoulders demonstrated subchondral changes in the right humeral head (Fig. 2C) and a linear area of subchondral change involving the left humeral head (Fig. 2D) consistent with AVN, as well as a bilateral high-grade supraspinatus tear and acromioclavicular joint osteoarthritis. He was treated with an intraarticular methylprednisolone 40-mg injection to both shoulders, with subsequent improvement of the pain and joint mobility. He also underwent a coronary artery bypass graft surgery for 3-vessel disease. The patient has otherwise maintained normal urine and salivary cortisol levels off osilodrostat or hydrocortisone, and 1 year after surgery, the ACTH (cosyntropin) stimulation test was normal. The pulmonary nodule has remained stable on serial imaging.

Table 2.

Postoperative cortisol and ACTH levels

Postoperative day
Lab Reference Range Conventional units (Système International units) 1 2 2 3 4 5
Morning cortisol 3.7-19.4 μg/dL (102.08- 535.21 nmol/L) 26 μg/dL (717.29 nmol/L) 21.5 μg/dL (593.14 nmol/L) 6 μg/dL (165.53 nmol/L) 8.1 μg/dL (223.46 nmol/L) 16.4 μg/dL (452.44 nmol/L) 21.5 μg/dL (593.14 nmol/L)
ACTH 7.2-63.3 pg/mL (1.58- 13.93 pmol/L) 72 pg/mL (15.84 pmol/L) 62 pg/mL (13.64 pmol/L)

Table 3.

Titration of osilodrostat treatment based on cortisol levels

Postoperative week
Lab Reference range Conventional units (Système International units) 8 9 11 13 15 18 22 24
ACTH 7.2-63.3 pg/mL (1.58-13.93 pmol/L) 95.6 pg/mL (21.03 pmol/L) 131 pg/mL (28.82 pmol/L) 58.8 pg/mL (12.94 pmol/L) 79.3 pg/mL (17.45 pmol/L) 79.9 pg/mL (17.58 pmol/L) 73.4 pg/mL (16.15 pmol/L) 62 pg/mL (13.64 pmol/L) 71.5 pg/mL (15.73 pmol/L)
Morning cortisol 3.7-19.4 μg/dL (102.08-535.21 nmol/L) 23.9 μg/dL (659.35 nmol/L) 18.8 μg/dL (518.65 nmol/L) 6.6 μg/dL (182.08 nmol/L) 4.5 μg/dL (124.15 nmol/L) 3.3 μg/dL (91.04 nmol/L) 2.4 μg/dL (66.21) nmol/L 8.2 μg/dL (226.22. nmol/L) 4.1 μg/dL (113.11 nmol/L)
LNSC <0.010-0.090 μg/dL (0.28-2.48 nmol/L) 0.615 μg/dL (16.97 nmol/L) 0.058 μg/dL (1.60 nmol/L) 0.041 μg/dL (1.13 nmol/L) 0.041 μg/dL (1.13 nmol/L)
UFC, 24-h 5-64 μg/24 h (137.94-1765.63 nmol/24 h) 246 μg/24 h (6786.65 nmol/24 h) 226 μg/24 h (6234.89 nmol/24 h) 2 μg/24 h (55.18. nmol/24 h)
Osilodrostat dose 2 mg BID 2 mg BID 2 mg AM
3 mg PM		 2 mg BID 2 mg AM
1 mg PM		 1 mg BID 1 mg daily Oslidrostat discontinued

Abbreviations: BID, twice per day; LNSC, late night salivary cortisol; UFC, urine free cortisol.

Discussion

Our patient exhibited pronounced hypercortisolism secondary to CD, with bilateral hip AVN as 1 of the presenting symptoms. Despite achieving biochemical remission of the disease and resolution of other associated symptoms, the patient was later diagnosed with bilateral shoulder AVN.

AVN caused by endogenous hypercortisolism is seldom documented, and routine screening for it is not typically conducted during the diagnosis of CS. However, AVN has been reported to be a presenting symptom in several case reports or may manifest years after the initial diagnosis [8]. Reported causes of AVN in endogenous CS include pituitary adenomas, adrenal adenomas or carcinomas, adrenal hyperplasia, or neuroendocrine tumors [8‐23] (Table 4), with some cases of AVN associated with severe hypercortisolism [10, 15]. Other risk factors associated with AVN include hip trauma, femoral fractures, hip dislocation, systemic lupus erythematosus in the setting of concomitant corticosteroid treatments, or vasculitis, sickle cell disease, hypercoagulability, Gaucher disease, hyperlipidemia or hypertriglyceridemia, hyperuricemia, hematological malignancies, antiretroviral medications, alcohol use, and exogenous steroid treatment [4]. Our patient had no history of hip trauma or other aforementioned comorbidities. Furthermore, during presentation, his lipid levels were normal, with low-density lipoprotein cholesterol of 89 mg/dL (<130 mg/dL) and triglycerides of 97 mg/dL (<150 mg/dL). Therefore, it is likely that his bilateral hip and shoulder AVN was caused by severe endogenous hypercortisolism.

Table 4.

Published cases of avascular necrosis in patients with endogenous hypercortisolism

First author, year Age (y)/sex Time of diagnosis in relation to CS diagnosis AVN related symptoms Imaging modality Imaging description Diagnosis Treatment
Salazar D, 2021 [15] 38 F 3 y prior to diagnosis Right hip pain MRI
  • Right hip joint effusion and synovitis
  • Flattening of the femoral head-Subcortical edema
 Adrenal adenoma Right hip arthroplasty
Madell SH, 1964 [16] 41 F 1 month before diagnosis Right shoulder pain X-ray
  • Increased density of the right humeral head with spotty areas of radiolucency
  • Early flattening and beginning of fragmentation
 Adrenal adenoma Osteotomy
Anand A, 2022 [21] 47 M Bilateral hip pain MRI
  • Necrosis of bilateral femur heads
 adrenocortical carcinoma
Belmahi N, 2018 [9] 28 F Progressive limping and right hip pain MRI
  • Right femoral head AVN
 Pituitary adenoma Right total hip replacement
Wicks I, 1987 [10] 39 M 18 months before diagnosis Progressive hip pain and stiffens X-ray
Bone scan
  • Lucent and sclerotic regions within flattened femoral heads
  • Some loss of articular cartilage
 Pituitary adenoma Conservative management
Koch C, 1999 [11] 30 F Sudden onset of severe left hip pain MRI
  • Abnormal high intensity signal changes in the bone marrow of the left femoral head
  • Joint effusion
  • Stage 2 AVN
 Pituitary adenoma Immediate core decompression surgery with decongestion of the left femoral head
Premkumar M, 2013 [12] 26 F 2 y after pituitary surgery for Cushing, while on replacement steroid therapy Progressive bilateral hip pain resulting in difficulty in walking MRI
  • Bilateral multiple bony infarcts in the proximal femur and distal femur
  • Femoral head collapse fractures -Stage 2 avascular necrosis
 Pituitary adenoma
Bauddh N, 2022 [13] 24 M 2 y prior to diagnosis Progressive left hip pain and difficulty in walking X-ray
MRI
  • Left femoral head AVN
 Pituitary adenoma Planned for surgery of hip AVN
Joseph A, 2022 [14] 21 F 1 y prior to diagnosis Bilateral hip joint pain X-ray
MRI
  • Ill-defined mixed sclerotic and lytic pattern of the femoral heads
  • Cortical disruption of the round contour
  • Low signal intensity in the subchondral region of the femoral necks on T1-weighted images
 Pituitary adenoma Planned for total hip replacement.
Bisphosphonates.
Pazderska A, 2016 [19] 36 F Right leg pain MRI
  • Bilateral AVN of the femoral heads
  • Left femoral head with early bone fragmentation
 Bilateral primary pigmented micronodular adrenal disease Spontaneous healing of AVN after adrenalectomy.
Papadakis G, 2017 [22] 55 F MRI
PET/CT 68Ga-DOTATATE
  • Bilateral AVN
  • Bone marrow edema extending to the intertrochanteric area
  • Mild subchondral femoral head collapse of the left hip
  • Increased activity in bilateral femoral heads and in the bone marrow consistent with edema
  • Mild left femoral head collapse
 Ectopic ACTH- secreting tumor
Phillips K, 1986 [8] 24 F 4.5 y after diagnosis Right femoral AVN X-ray
  • Flattening and sclerosis of femoral head
 Cushing disease
25 F 4 y after diagnosis Right femoral AVN
  • Subchondral lucency
43 F 8 mo after diagnosis Right humeral AVN
  • Sclerosis and flattening of articular surface of humeral head
61 F 11 y after diagnosis Left femoral AVN and bilateral humeral heads
  • Cortical indistinctness and subchondral lucency
  • Left humeral head flattening and sclerosis
Cerletty J, 1973 [20] 54 M 3 mo before diagnosis Right femoral head fracture X-ray
  • Bilateral subchondral sclerosis of the femoral heads
  • Some narrowing of the joint space on the left
  • Infraction of the margin of the right femoral head
  • Femoral neck fracture.
 Bilateral adrenal cortical hyperplasia Total hip joint arthroplasty
Ha J-S, 2019 [18] 36 F 2 y before diagnosis 2 mo left hip restricted range of motion X-ray
MRI
  • Right femoral head with areas of hyperlucency and surrounding sclerosis
  • Subtle changes in the shape of the articular surface
  • Bilateral femoral head osteonecrosis -Increased amount of joint fluid and bone marrow edema in the left hip
  • Right femoral head necrosis
 Adrenal cortical adenoma Total hip replacement
Takada, J, 2004 [17] 55 F Intense right hip pain and a limp MRI
  • Low-intensity band on T1-weighted images
  • Stage 2 AVN.
 Adrenal adenoma Total hip arthroplasty
Modlinger RS, 1972 [23] 69 F Increased pain of right shoulder X-ray
  • Bilateral shoulders with aseptic necrosis of the humeral heads
 Ectopic ACTH secretion NET form pancreatic tumor

Abbreviations: AVN, avascular necrosis; F, female; M, male; MRI, magnetic resonance imaging; NET, neuroendocrine tumor.

AVN can result in irreversible femoral head collapse, leading to severe limitation in movement, reduced joint functionality, and decreased quality of life [24]. Initially, patients may be asymptomatic or endorse nonspecific pain when presenting with AVN and may not be diagnosed until an advanced stage when they develop more severe pain and disability [25]. In a meta-analysis assessing the prevalence of AVN in patients with systemic lupus erythematosus, including those who received corticosteroid treatment, asymptomatic AVN was detected in 29% of patients and symptomatic disease was noted in 9% [26]. AVN can diagnosed with MRI or CT imaging. Although noncontrast MRI has higher sensitivity and specificity in detecting early stages of the disease, CT is comparable to MRI in more advanced stages. Ancillary imaging modalities include plain radiography, positron emission tomography, and bone scan [27].

Staging of AVN relies on radiologic features and size of lesions. In earlier stages, imaging can be normal (stage 0) or with subtle abnormalities on MRI or bone scan and normal radiography (stage 1). As the disease progresses, structural changes, including cystic and sclerotic changes (stage 2), subchondral collapse (stage 3), flattening of the femoral head (stage 4), joint narrowing and acetabular changes (stage 5), and, finally, advanced degenerative changes (stage 6) can be detected on most imaging modalities.

Management of early stages of AVN includes observation or conservative weight-bearing management, medical therapy with bisphosphonates, anticoagulation therapy, statins, and vasodilators. Invasive procedures such as mesenchymal stem cells implantation, osteotomy, surgical joint decompression, and total hip replacement are reserved for more advanced stages [28]. Indeed, AVN accounts for approximately 10% of total hip replacements in the United States [29]. Staging has prognostic implications for treatment options and disease outcomes. Early-stage disease, when diagnosed and treated, can often regress, and be cured. Conservative measures, medical treatment, biophysical stimulation, extracorporeal shockwave therapy, or core decompression, can prevent femoral head collapse and further hip arthroplasty. On the other hand, late-stage disease, characterized by joint collapse, is irreversible and often requires joint replacement [30].

Although actual prevalence rates of AVN in endogenous CS is unknown, one should consider screening for AVN in this high-risk population, particularly in patients showing markedly elevated cortisol levels, as in our case. Such an approach would facilitate the early identification of individuals who would benefit from earlier medical or surgical interventions, thereby preventing permanent joint destruction and chronic disability.

Learning Points

  • AVN can be a complication of endogenous hypercortisolism.
  • AVN may present asymptomatically or with nonspecific symptoms such as joint pain.
  • AVN can affect multiple joints, including hips and shoulders, and its early diagnosis relies on MRI or CT imaging.
  • Early detection and intervention for AVN are crucial to prevent irreversible joint damage and disability.
  • Screening for AVN in patients with CS should be considered to enable timely intervention and prevent long-term complications, particularly in patients with hip or shoulder pain and severe hypercortisolism.

Contributors

All authors made individual contributions to authorship. N.T. and O.C. were involved in the diagnosis and management of the patient and manuscript submission. S.B. was involved in the histopathology section and preparation of histology images. T.L. was involved in the interpretation and preparation of the radiology images. A.N.M. was responsible for the patient’s surgery and treatment plan. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

Dr. Odelia Cooper is an Editorial Board member for JCEM Case Reports and played no role in the journal’s evaluation of the manuscript. There are no other disclosures to declare.

Informed Patient Consent for Publication

Signed informed consent obtained directly from patient.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

  • AVN

    avascular necrosis

  • CD

    Cushing disease

  • CS

    Cushing syndrome

  • CT

    computed tomography

  • MRI

    magnetic resonance imaging

© 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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From Weight Gain To Diabetes

Posted on March 10, 2025 by MaryO
Cushing’s syndrome happens when the body has too much cortisol, the stress hormone. It can cause weight gain, high blood pressure, and diabetes. So how to keep your health in check and what are the treatment options available? In an exclusive interview with Times Now, an Endocrinologist explains its symptoms, causes, and treatments.
We often blame stress for everything—from sleepless nights to stubborn weight gain. But did you know your body’s stress hormone, cortisol, could be at the root of more serious health issues like high blood pressure and diabetes? Yes, you read that right! But how? We got in touch with Dr Pranav A Ghody, Endocrinologist at Wockhardt Hospital, Mumbai Central, who explains how excessive cortisol levels can lead to a condition known as Cushing’s Syndrome.
What Exactly is Cortisol, and Why is it Important?
Hormones are the body’s chemical messengers, travelling through the bloodstream to regulate essential functions. Among them, cortisol, produced by the adrenal glands (tiny glands sitting above the kidneys), plays a crucial role in controlling blood pressure, blood sugar, energy metabolism, and inflammation. The pituitary gland, located at the base of the brain, regulates cortisol through another hormone called Adrenocorticotropic Hormone (ACTH).
Often referred to as the “stress hormone,” cortisol spikes when we’re under stress. However, when levels remain high for too long, it can lead to Cushing’s Syndrome, a disorder first identified in 1912 by Dr Harvey Cushing.

What Causes Cushing’s Syndrome?

Dr Ghody explains that Cushing’s Syndrome occurs when the body is exposed to excessive cortisol, which can happen in two ways:

1. Exogenous (External) Cushing’s Syndrome
This is the most common form and results from prolonged use of steroid medications (such as prednisone) to treat conditions like asthma, rheumatoid arthritis, and lupus, or to prevent transplant rejection. Since steroids mimic cortisol, long-term use can disrupt the body’s hormone balance.
2. Endogenous (Internal) Cushing’s Syndrome
This occurs when the body produces too much cortisol due to a tumour in the pituitary gland, adrenal glands, or other organs (lungs, pancreas, thymus). While rare—affecting about 10 to 15 people per million annually—it’s more common in women between 20 and 50 years old. When caused by a pituitary tumour, it’s specifically called Cushing’s Disease.

Symptoms: How To Recognize Signs Of Cushing’s Syndrome

Excess cortisol affects multiple organs, leading to a variety of symptoms. This includes:

– Weight gain around the belly (central obesity)
– Rounded, puffy face (moon face)
– Excess facial and body hair (hirsutism)
– Fat accumulation on the upper back (buffalo hump)
– Thin arms and legs
– Dark red-purple stretch marks on the chest and abdomen
– Extreme fatigue and muscle weakness
– Depression or anxiety
– Easily bruising with minimal trauma
– Irregular menstrual cycles in women
– Reduced fertility or low sex drive
– Difficulty sleeping
High blood pressure and newly diagnosed or worsening diabetes are also common red flags.

Why is Cushing’s Syndrome Often Misdiagnosed?

Dr Ghody explains that while severe cases of Cushing’s Syndrome are easier to identify, milder forms can often be missed or mistaken for conditions like obesity, diabetes, or polycystic ovary syndrome (PCOS).

Diagnosing Cushing’s Syndrome involves:
1. Measuring cortisol levels in the blood, urine, or saliva.
2. Identifying the source through ACTH hormone testing, MRI/CT scans, and advanced techniques like Inferior Petrosal Sinus Sampling (IPSS) or nuclear medicine scans
Treatment Options: How is Cushing’s Syndrome Managed?
Once diagnosed, the treatment depends on the cause:
– If due to steroid medication, the dosage is gradually reduced under medical supervision.
– If caused by a tumour, surgery is the primary treatment. Some patients, especially those with pituitary tumours, may require repeat surgery, gamma knife radiosurgery, or medications to control cortisol levels.

Can You Prevent Cushing’s Syndrome?

While complete prevention isn’t always possible, Dr Ghody shares some key strategies to reduce risk:

– Use steroids cautiously – If prescribed, take the lowest effective dose for the shortest time. Never stop abruptly without consulting a doctor.
– Genetic screening for people at risk – If you have a family history of pituitary or adrenal tumours, regular monitoring can help with early detection.
– Maintain a healthy lifestyle – A diet rich in fresh vegetables, and fruits, low sodium intake, adequate calcium, and vitamin D can help manage the metabolic effects of excess cortisol.
– Avoid alcohol and tobacco – These can further disrupt hormone balance and overall health.
“Cushing’s Syndrome can be life-threatening if left untreated, but early diagnosis and proper management can significantly improve quality of life. So if you experience unexplained weight gain, blood pressure spikes, or other symptoms, consult an endocrinologist to manage hormonal imbalances,” he said.

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Older Adults With Cushing’s Disease Present With Fewer Symptoms Than Younger Patients

Posted on March 7, 2025 by MaryO

Key takeaways:

  • Older age was tied to a higher prevalence of 10 comorbidities among a group of 608 people with Cushing’s disease.
  • Younger age was associated with most hallmark features of Cushing’s disease.

The presentation of Cushing’s disease varies by age, with older adults having fewer hallmark features of the condition and more comorbidities, according to study findings published in The Journal of Clinical Endocrinology & Metabolism.

Researchers assessed data from 608 people diagnosed with Cushing’s disease and treated with a transsphenoidal tumor resection at 11 academic pituitary centers in the U.S. from 2003 to 2023 (82% women; 77.3% white). Patients were divided into 10-year age interval groups, with the youngest group consisting of those aged 10 to 19 years and the oldest containing adults aged 70 to 79 years. Researchers found Cushing’s disease presents differently as adults age, with older adults experiencing more comorbidities and complications, but fewer hallmark features such as weight gain, facial rounding and hirsutism.

“The diagnosis of Cushing’s disease remains challenging, particularly with age,” Won Kim, MD, associate clinical professor of neurosurgery and radiation oncology at the David Geffen School of Medicine at UCLA, told Healio. “The older a patient is, the more likely that he or she may have a slower-growing tumor with fewer classic manifestations of the disease.”

Kim and colleagues obtained data from the Registry of Adenomas of the Pituitary and Related Disorders. Hallmark features of Cushing’s disease were identified by consensus opinion.

The number of comorbidities increased with patient age (beta = 0.0466; P < .001), according to the researchers.

Older age was associated with several comorbidities for patients with Cushing’s disease, including hypertension (P < .001), diabetes (P < .001), hyperlipidemia (P < .001), cancer (P < .001), coronary artery disease (P < .001), chronic obstructive pulmonary disease (P = .044), cardiac arrhythmia (P = .023), hepatitis (P = .038), anxiety (P = .039) and osteopenia (P = .024). The most common comorbidity was hypertension, which was prevalent in 67.2% of participants.

In an analysis of presenting hallmark features of Cushing’s disease, younger age was positively associated with weight gain (P < .001), facial rounding (P < .001), abdominal striae (P < .001), hirsutism (P < .001), menstrual irregularities (P < .001) and acne (P < .001). Older age was positively tied to obstructive sleep apnea (P = .007). The most common hallmark feature of Cushing’s disease was weight gain, prevalent in 80.2% of patients.

“Our work highlights that we must lower our threshold for suspecting Cushing’s disease in patients without the classic physical manifestations as the age of the patient increases,” Kim said in an interview. “Subtle clues, such as increasingly difficult to control medical conditions such as hypertension and diabetes, may be the only things we see.”

Older age was associated with lower preoperative 24-hour urinary free cortisol levels (beta = –0.0256; P = 6.89 x 10-7), but higher postoperative nadir cortisol (beta = 0.0342; P = 1.03 x 10-4) and higher adrenocorticotropin (beta = 0.0204; P = 5.22 x 10-4).

In an assessment of tumor characteristics, older age was tied to having a higher Knosp grade tumor (beta = 0.011; P = .00435), greater tumor volume (beta = 0.0261; P = .0233) and higher maximum tumor dimension (beta = 0.009; P = 3.82 x 10-4). Older age was inversely associated with Ki-67 index, which is a measure of tumor’s proliferation (beta = –0.0459; P = 1.39 x 10-4).

Age was not associated with a patient’s number of surgical complications. Older age was linked to a greater prevalence of deep vein thrombosis or venous thromboembolism (beta = 0.07; P = .014). Younger age was tied to a higher prevalence of postoperative arginine vasopressin (beta = –0.02; P = .048).

Kim said the study’s findings should encourage health care professionals to adjust their methods for screening for Cushing’s disease in older adults.

“Improving our diagnostic sensitivity through our standardized assessments for the disease should account for these new findings,” Kim told Healio.

For more information:

Won Kim, MD, can be reached at wonkim@mednet.ucla.edu.

Published by:endocrine today logo

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Impact of Remission Status in Endogenous Cushing’s Syndrome on Cancer Incidence

Posted on March 4, 2025 by MaryO

Abstract

Objective
Endogenous Cushing’s syndrome (CS) has been linked with an increased risk of cancer. We aimed to evaluate the association between cancer risk and disease remission post-surgery in adrenal CS and Cushing’s disease (CD).
Design
A nationwide retrospective matched-cohort study of patients with CS diagnosed between 2000-2023 in Israel, using Clalit Health Services’ database. Methods Patients with CS were matched 1:5 with controls by age, sex, socioeconomic status, and BMI. Remission status post-surgery was assessed within two years after the diagnosis of CS. The outcome measured was time to first diagnosis of malignancy, at least three years post-CS diagnosis, excluding those who died or developed cancer earlier. Malignancy risk, stratified by remission status, was evaluated using Cox proportional hazards with death as a competing event.
Results
The cohort comprised 388 cases and 1,862 controls [mean age at diagnosis, 47.4±16.8 years; 1,534 (68.2%) women]. Among patients with CD, those who did not achieve remission within 2 years post diagnosis (n=69) had a higher risk of malignancy compared to those who achieved remission (n=99) (HR 3.89, 95% CI 1.41-10.75). Cancer risk in patients with CD who achieved remission was similar to that of the controls (HR 0.58, 95% CI 0.23-1.47). In patients with adrenal CS, the risk of cancer was comparable between those who did not achieve early remission (n=39) and those who did (n=113) (HR 1.68, 95% CI 0.83-3.40).
Conclusion
Though cancer risk is higher in both CD and adrenal CS, we have shown that achieving surgical remission within 2 years may attenuate cancer risk in patients with CD, but not in those with adrenal CS.

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