Pregnancy Case: Cushing’s Syndrome with Diabetes Insipidus

Posted on September 3, 2025 by MaryO

Cushing’s Syndrome, a rare but complex endocrine disorder characterized by excessive cortisol production, presents unique challenges and risks during pregnancy. Recent advancements in medical understanding have led to greater awareness of the implications of this syndrome when coupled with conditions like diabetes insipidus, particularly in pregnant patients. The coexistence of these disorders emphasizes the need for a multidisciplinary approach to manage these high-risk pregnancies effectively.

In a groundbreaking case report published in BMC Endocrine Disorders, researchers Hata et al. provide an illuminating examination of a pregnant patient diagnosed with Cushing’s Syndrome along with diabetes insipidus. This syndromic constellation is particularly alarming considering the metabolical and physiological adaptations that occur during pregnancy. The researchers delve deeply into the complexities presented by this rare overlap, offering insight into potential therapeutic pathways and management strategies.

Cushing’s syndrome is often the result of pituitary adenomas or adrenal tumors that result in a hypercortisolemic state. When analyzing its manifestation during pregnancy, clinicians are faced with the delicate balance of managing both maternal and fetal health. In this compelling case, the authors explore the detrimental effects of high cortisol levels and the complications that arise from diabetes insipidus on maternal health.

Diabetes insipidus in pregnancy can further complicate the management of Cushing’s syndrome. It is primarily characterized by an inability of the kidneys to concentrate urine due to a deficiency in the antidiuretic hormone (ADH). This disorder can lead to severe dehydration, electrolyte imbalances, and complications such as preterm labor or uterine atony. By detailing the clinical features of the patient, the report underscores the need for vigilant monitoring and timely interventions to prevent adverse outcomes.

Central to the case is the interplay between the hormonal milieu of pregnancy and the pathological processes of Cushing’s syndrome. The physiological increase in cortisol can mask or exacerbate the symptoms of diabetes insipidus. Thus, clinicians must be astute in recognizing the overlays of these conditions to adjust management plans accordingly. This is especially critical in the prenatal period, where traditional approaches might clash with the unique requirements of pregnancy.

Therapeutic management for such patients is multifaceted. Close collaboration among obstetricians, endocrinologists, and neonatologists is essential to ensure that both maternal and fetal welfare are prioritized. This case illustrates the complexity involved in choosing appropriate pharmacotherapy while minimizing risks to the developing fetus. Importantly, the authors suggest that non-invasive monitoring techniques may help in realizing a safer management regime.

The psychological impact on mothers grappling with these intertwined conditions cannot be overstated. The report sheds light on the emotional strain that awaits patients who must anticipate the uncertainties surrounding their pregnancies. Understanding these layers can aid healthcare providers in offering holistic support not just medically, but psychologically as well.

An often-overlooked aspect of such complex cases is the significance of postnatal follow-up. After delivery, the management of Cushing’s Syndrome may need reevaluation as hormonal levels return to baseline. In this case, the potential resolution of diabetes insipidus after childbirth rejuvenates discussions regarding long-term monitoring and treatment adherence, ensuring that mothers receive the care they need as they transition into motherhood.

Women with Cushing’s Syndrome and diabetes insipidus can experience heightened fatigue, which complicates the already demanding experience of pregnancy. The authors advocate for the integration of lifestyle modifications and supportive measures to help manage energy levels, further illustrating the multifaceted management required in such cases. These alterations can significantly contribute to improving the quality of life for these women in an already challenging scenario.

The ethical considerations surrounding the treatment of pregnant patients with rare syndromes add another layer of complexity. The authors emphasize the importance of informed consent, particularly as clinical decisions might involve experimental therapies or interventions that are not standard for pregnant patients. Open dialogues between patients and providers about risks and benefits can lead to better decision-making processes tailored to individual patient needs.

In conclusion, Hata et al.’s illuminating case report on Cushing’s Syndrome with diabetes insipidus in pregnancy serves as a pivotal reference for clinicians navigating the complexities of these coexisting conditions. As medical science continues to evolve, the insights offered in this report will undoubtedly inform best practices for managing intricate cases, further enhancing maternal-fetal medicine. The need for ongoing research and clinical trials remains crucial as we strive to optimize pregnancy outcomes in patients suffering from this rare combination of disorders.

As we look toward the future, the challenges presented by these conditions urge the medical community to prioritize collaborative care models, innovative therapeutic strategies, and comprehensive support systems for affected patients. While this case report sheds light on the clinical intricacies involved, it also heralds a call to action for further exploration into Cushing’s Syndrome and its implications in pregnancy, ensuring that mothers receive the best possible care during one of life’s most critical journeys.

Subject of Research: Cushing’s Syndrome with diabetes insipidus in pregnancy

Article Title: Cushing’s Syndrome with diabetes insipidus in pregnancy: a case report

Article References:

Hata, S., Shinokawa, N., Harada, Y. et al. Cushing’s Syndrome with diabetes insipidus in pregnancy: a case report.
BMC Endocr Disord 25, 197 (2025). https://doi.org/10.1186/s12902-025-01946-9

Image Credits: AI Generated

DOI: 10.1186/s12902-025-01946-9

Keywords: Cushing’s Syndrome, diabetes insipidus, pregnancy, maternal-fetal medicine, endocrine disorders, case report, hypercortisolism, antidiuretic hormone, multidisciplinary approach, healthcare management.

From https://bioengineer.org/pregnancy-case-cushings-syndrome-with-diabetes-insipidus/

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Unilateral Adrenalectomy for Pediatric Cyclical Cushing Syndrome With Novel PRKAR1A Variant Associated Carney Complex

Posted on September 2, 2025 by MaryO

Abstract

Primary pigmented nodular adrenocortical disease is a rare cause of Cushing syndrome accounting for less than 1% of cases. We present a 9-year-old boy who presented at age 4 with cyclical Cushing syndrome and was eventually diagnosed with a novel, previously unreported, unpublished variant in PRKAR1A associated with Carney complex. He was treated with unilateral left adrenalectomy. At 1-year follow-up, he continues to be in remission of his symptoms of Cushing syndrome.

Introduction

Cushing syndrome is characterized by prolonged exposure to excess glucocorticoids and is broadly classified as either ACTH-dependent or ACTH-independent [1, 2]. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome, characterized by bilateral adrenal hyperplasia with autonomous, hyperfunctioning nodules [1, 2]. Approximately 90% of PPNAD cases occur in the context of Carney complex, with isolated cases being exceedingly uncommon [1, 2].

PPNAD was first described in 1984 by Carney et al, who coined the term in a case series of 4 patients and a review of 24 previously reported cases [1]. In that series, patients presented with ACTH-independent Cushing syndrome and no radiographic evidence of adrenal tumors. All underwent bilateral adrenalectomy, with histopathology revealing bilateral pigmented nodules in otherwise small or normal-sized adrenal glands [1]. Histologically, the classic features of PPNAD include multiple small black or brown cortical nodules surrounded by an atrophic adrenal cortex—reflecting chronic ACTH suppression [1].

Clinically, PPNAD most often presents with cyclical Cushing syndrome, characterized by alternating periods of hypercortisolism and normocortisolemia [2]. This intermittent pattern poses a substantial diagnostic challenge, as biochemical confirmation requires detection of cortisol excess during active phases of the cycle.

Carney complex is a multiple neoplasia syndrome involving endocrine, cardiac, cutaneous, and neural tumors. First described by Carney et al in 1985, it is typically inherited in an autosomal dominant fashion. Approximately 70% of cases occur in familial settings, while the remaining 30% arise from de novo pathogenic variants [3, 4]. Over half of affected individuals harbor pathogenic variants in the PRKAR1A tumor suppressor gene on chromosome 17q24.2, while approximately 20% of cases are linked to alternate loci such as 2p16 [2, 4].

Diagnostic criteria for Carney complex include either 2 clinical manifestations or 1 clinical manifestation in combination with a pathogenic PRKAR1A variant or an affected first-degree relative [2]. The most common endocrine manifestation is PPNAD, reported in approximately 25% of patients with Carney complex, though this likely underestimates the true prevalence, as autopsy studies reveal histologic evidence of PPNAD in nearly all affected individuals [2].

The Endocrine Society clinical practice guidelines recommend bilateral adrenalectomy as the definitive treatment for PPNAD, effectively curing hypercortisolism but necessitating lifelong glucocorticoid and mineralocorticoid replacement therapy due to resultant adrenal insufficiency [5]. Unilateral adrenalectomy has emerged as an alternative approach, particularly in pediatric patients, with the potential to preserve endogenous adrenal function.

Herein, we present the case of a 9-year-old boy with Carney complex and cyclical Cushing syndrome due to PPNAD, successfully managed with unilateral adrenalectomy.

Case Presentation

A 4-year-old boy presented with a week-long history of facial swelling, hyperphagia, weight gain, and scrotal swelling. At presentation, his weight was 22 kg (99th percentile) and body mass index (BMI) was 18 kg/m² (96th percentile). Initial workup revealed normal 24-hour urinary free cortisol <0.0913 µg/day (SI: 274 nmol/day) with low urinary creatinine 215 mg/day (SI: 1.9 mmol/day) (normal reference range 973-2195 mg/day; SI: 8.6-19.4 mmol/day) suggesting an incomplete sample. A repeat collection produced similar results. A 1 mg dexamethasone suppression test demonstrated nonsuppressed cortisol (27.9 µg/dL; SI: 772 nmol/L), suggestive of Cushing syndrome.

Over 5 years, the patient experienced 2 to 3 episodes per year of rapid weight gain (20-50 lbs), facial flushing, abdominal distention, and mood changes. Despite persistent obesity (>97th percentile), linear growth remained normal.

Diagnostic Assessment

At age 7, midnight salivary cortisol was markedly elevated at 3.7 µg/dL (SI: 103 nmol/L) (normal reference range < 0.4 µg/dL; SI: < 11.3 nmol/L), raising suspicion for cyclical Cushing syndrome. Magnetic resonance imaging of the abdomen was negative for adrenal lesions. At age 8, during an active episode, 2 elevated salivary cortisol samples, 2.0 µg/dL (SI: 55.1 nmol/L) and 2.2 µg/dL (SI: 61.9 nmol/L) (normal reference range < 0.4 µg/dL; SI: < 11.3 nmol/L), were obtained. A high-dose dexamethasone suppression test yielded a low baseline cortisol 3.2 µg/dL (SI: 89 nmol/L) and nonsuppressed cortisol post-dexamethasone 3.0 µg/dL (SI: 83 nmol/L). Baseline ACTH was 7.7 pg/mL (SI: 1.7 pmol/L), suppressed to <3.2 pg/mL (SI: < 0.7 pmol/L) post-dexamethasone—consistent with ACTH-independent cortisol excess.

At age 9, the patient underwent the gold standard diagnostic testing for cyclical Cushing, the Liddle test. The test involves 6 days of urine collection: days 1 to 2 establish baseline urinary cortisol levels, days 3 to 4 assess response to low-dose dexamethasone, and days 5 to 6 evaluate response to high-dose dexamethasone. The patient’s cortisol increased paradoxically from 118.5 µg/day (SI: 327 nmol/day) to 402.0 µg/day (SI: 1109 nmol/day) over 6 days, consistent with PPNAD physiology. Genetic testing was performed with the following report: “A heterozygous variant, NM_002734.4(PRKAR1A):c.550-2_553delinsG, p.(Val184_Tyr185delinsAsp), was detected in exon 7 of this gene. This variant does not appear to have been reported in population (gnomAD, ESP, dbSNP) and clinical databases (ClinVar), or in the literature. The impact of this variant on RNA splicing as assessed by multiple algorithms (Alamut Suite) is: abolishment of canonical acceptor splice site. Based on the current evidence, this variant was classified as likely pathogenic, American College for Medical Genetics category 2”. Family testing revealed this to be a de novo pathogenic variant.

Further workup included echocardiogram and thyroid ultrasound, both of which were normal. During workup for scrotal swelling at initial presentation, the patient was found to have bilateral testicular masses with negative testicular cancer tumor markers: α-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase. The family declined invasive biopsy of these lesions. He was followed by pediatric urology with yearly serial ultrasound, and these were felt to be benign testicular tumors, presumed noncalcifying Sertoli cell tumors, associated with Carney complex (Fig. 1).

 

Ultrasound of bilateral testicular lesions. A) Left testicle. B) Right testicle.

Figure 1.

Ultrasound of bilateral testicular lesions. A) Left testicle. B) Right testicle.

Based on the presence of 2 major diagnostic criteria in combination with the molecular diagnosis of a likely pathogenic variant of PRKAR1A, the diagnosis of Carney complex was established.

Treatment

The patient was referred for surgical evaluation for consideration of adrenalectomy. A comprehensive discussion was conducted regarding the potential benefits and risks of unilateral vs bilateral adrenalectomy. The family was counseled that unilateral adrenalectomy might not fully resolve the hypercortisolemia and that a subsequent contralateral adrenalectomy could be necessary. In contrast, bilateral adrenalectomy would definitively address cortisol excess but result in permanent adrenal insufficiency requiring lifelong glucocorticoid and mineralocorticoid replacement. After multidisciplinary consultation with endocrinology and surgery, the decision was made to proceed with unilateral adrenalectomy.

Preoperative IV contrast-enhanced computed tomography (CT), reviewed by a physician experienced in PPNAD, demonstrated greater nodularity in the left adrenal gland compared to the right. Therefore, a laparoscopic left adrenalectomy was performed electively without intraoperative complications. The patient was discharged on postoperative day 1. At the time of surgery (age 9), his weight was 70 kg (100th percentile), and BMI was 31.6 kg/m² (99th percentile). The resected left adrenal gland was submitted for histopathologic evaluation. Gross examination revealed no overt nodularity (Fig. 2); however, microscopic analysis identified multiple pigmented cortical nodules consistent with PPNAD (Fig. 3).

 

Left adrenal gland gross morphology. No macroscopic nodularity appreciable.

Figure 2.

Left adrenal gland gross morphology. No macroscopic nodularity appreciable.

 

Hematoxylin and Eosin staining on microscopy of left adrenal gland demonstrating hyperpigmented nodule.

Figure 3.

Hematoxylin and Eosin staining on microscopy of left adrenal gland demonstrating hyperpigmented nodule.

Outcome and Follow-up

The patient was followed closely in the postoperative period and was last evaluated 11 months after adrenalectomy. He remained clinically well, with complete resolution of Cushingoid features and no evidence of recurrence. Since surgery, he had experienced significant weight loss of 11.4 kg, with a current weight of 58.6 kg and a BMI of 25 kg/m² (97th percentile).

In summary, this case describes a 9-year-old boy with ACTH-independent, cyclical Cushing syndrome secondary to PPNAD, associated with a de novo likely pathogenic variant in the PRKAR1A gene, consistent with Carney complex. Histopathologic analysis of the resected adrenal gland confirmed the diagnosis of PPNAD. At nearly 1 year post-unilateral adrenalectomy, the patient remains asymptomatic with no biochemical or clinical signs of disease recurrence.

Discussion

Diagnosis of cyclical Cushing is challenging due to the cyclical nature of the disease and the challenges with current available testing modalities. Late-night salivary cortisol testing was a more reliable screening tool in this case as the 24-hour urinary cortisol were affected by inaccurate collection. The cyclical nature of the disease, coupled with the necessity for appropriately timed testing, contributed to a prolonged interval before definitive diagnosis and treatment. Additionally, initial imaging was interpreted as normal, and it was only upon review by a clinician with expertise in PPNAD that subtle adrenal nodularity was identified on CT. Ultimately, the Liddle test and genetic testing were the highest yield for confirmation of disease. This test measures the suppressibility of endogenous cortisol following exogenous dexamethasone administration. In patients with PPNAD, a paradoxical increase in cortisol excretion may occur, attributed to glucocorticoid receptor–mediated activation of protein kinase A catalytic subunits [6]. The likely pathogenic variant found in this case is a novel, previously unreported, variant in the PRKAR1A gene. This rare variant impact both the canonical acceptor splice site in intron 6 as well as results in an in-frame protein change in exon 7 (Val184_Tyr185delinsAsp).

The treatment of PPNAD in the context of Carney complex is typically with bilateral adrenalectomy, as per Endocrine Society guidelines [5]. The drawback of bilateral adrenalectomy is the resultant adrenal insufficiency resulting in lifelong adrenal replacement. Unilateral adrenalectomy is an attractive option for the treatment of PPNAD given the ability to avoid adrenal insufficiency brought upon by bilateral adrenalectomy. Case reports and case series in adult patients have demonstrated variable success in unilateral treatment. In a case series of 17 patients with classic cyclical Cushing, 3 patients had recurrence of Cushing syndrome after unilateral adrenalectomy and were cured with contralateral adrenalectomy [7]. One patient had subtotal (<90%) left adrenalectomy and did not have recurrence with 66 years of follow-up [7].

A case series by Xu et al 2013 described 12 out of 13 patients with PPNAD successfully cured with unilateral adrenalectomy at median 47 months follow-up [8]. The side of adrenalectomy was selected based on CT/magnetic resonance imaging in 3 patients and adrenal iodine131-norcholesterol scintigraphy in the remaining. At our center, the iodine131-norcholesterol scintigraphy was not available so CT was the chosen imaging modality.

Ultimately, the efficacy and morbidity of unilateral adrenalectomy remains unclear. Furthermore, due to the rarity of PPNAD, the criteria for selection of patients who are candidates for unliteral adrenalectomy is challenging to establish. This case reports adds to the existing literature the clinical characteristics of one patient treated successfully by unilateral adrenalectomy.

Learning Points

  • Diagnosis of cyclical Cushing can be very challenging. Late-night salivary cortisol is more reliable than 24-hour urinary cortisol.
  • The paradoxical rise in cortisol in the Liddle test is confirmatory for cyclical Cushing, hence the testing should be considered early in affected patients.
  • Genetic testing assessing for Carney complex, PRAKA1A pathogenic variant, should be considered early in a patient with concern for cyclical Cushing and another system involved like testicular lesions.
  • Although bilateral adrenalectomy is the recommendation for PPNAD; in selected patients, unilateral adrenalectomy might provide several years of remission.

Acknowledgements

Thank you to Dr. Hong Wang, MD, PhD, DABMGG, FACMG, FCCMG, for her support on this project and in all things. Thank you to Dr. Andre Lacroix MD, FCAHS, for reviewing the preoperative CT adrenals with the team.

Contributors

All authors made individual contributions to authorship. F.B. was involved in the diagnosis and management of the patient. N.S. was responsible for the patient’s surgery. C.J.Z. was involved in the patient’s surgery and postoperative care. R.S., M.S., and P.W. were all medical professionals involved in his management and care. All authors contributed, 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’s relatives or guardians

Data Availability Statement

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

Author notes

Natashia Seemann and Funmbi Babalola co-senior author.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
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A Case 0f Hailey–Hailey Disease Accompanied by Cushing’s Syndrome and Adrenal Insufficiency Due to Long-Term Usage of Topical Steroids With Review of Literature

Posted on August 14, 2025 by MaryO
Abstract

Hailey–Hailey disease (HHD), or familial benign chronic pemphigus, is a rare autosomal dominant disorder characterized by recurrent vesicles and erosions in intertriginous areas. Topical corticosteroids are the primary treatment, but their potential systemic side effects are often overlooked. Prolonged use on compromised skin can lead to excessive absorption, increasing the risk of iatrogenic Cushing’s syndrome and adrenal insufficiency.

Here, we report the case of a 50-year-old woman with HHD who had been using topical clobetasol or betamethasone for over 10 years, reaching doses up to 50 g/day.

She developed Cushingoid features, metabolic abnormalities, and suppression of the hypothalamic–pituitary–adrenal (HPA) axis. After tapering off topical corticosteroids, she developed adrenal insufficiency and associated withdrawal symptoms. Following the initiation of hydrocortisone replacement therapy, psychiatric symptoms, impaired glucose tolerance, and osteoporotic fractures emerged, suggesting exacerbation of iatrogenic Cushing’s syndrome.

This case highlights the risk of systemic complications from chronic topical corticosteroid use, particularly in high-absorption areas. Gradual dose reduction, close endocrine monitoring, and individualized tapering strategies are essential to prevent severe outcomes.

Clinicians should be aware of potential adrenal suppression and consider endocrine evaluation in patients receiving prolonged, high-dose topical corticosteroid therapy.

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Patient Finds Relief After Adrenal Gland Tumor Removed by Baylor Endocrine Surgeon

Posted on August 6, 2025 by MaryO

Hanna Pierce didn’t expect to learn she had a tumor on her adrenal gland during a CT scan. Just two weeks after delivering her second child and recovering from COVID-19, she went to urgent care with concerns about a possible blood clot. Instead, imaging revealed a tumor in her adrenal gland. “I didn’t have symptoms,” she said. “They were checking for something else and just happened to find it.”

That unexpected discovery in 2021 launched Pierce into a years-long journey that ultimately led to robotic surgery at Baylor Medicine with Dr. Feibi Zheng, an endocrine surgeon who specializes in treating adrenal tumors.

“Many people haven’t heard much about the adrenal glands,” said Zheng, assistant professor in the Division of Surgical Oncology. “They sit on top of the kidneys and produce hormones like cortisol that regulate everything from metabolism to the body’s stress response. If a tumor is overproducing cortisol, it can silently wreak havoc on the body over time.”

Doctors told Pierce that her tumor was consistently producing slightly elevated cortisol, a red flag. “My doctor told me if we left it alone, it could develop into diabetes or full-blown Cushing’s syndrome. At first, we just monitored it,” she said.

In the months and years that followed, Pierce did experience symptoms but attributed them to the demands of motherhood. “After my second child, I couldn’t lose weight no matter what I did. I had anxiety, constant fatigue in the afternoons, and I wasn’t sleeping well,” she recalled. “But I just chalked it up to being a mom of two.”

By 2024, her endocrinologist said it was time to act and referred her to Zheng, who confirmed the tumor was still producing excess cortisol. “Dr. Zheng told me I was going to feel so much better and explained what she was going to do,” Pierce said. “When I went to see her for the consultation, she was very informative. She didn’t pressure me to have surgery but explained everything to me.”

The Baylor Medicine endocrine surgery team, including Zheng and supported by physician assistant Holly Clayton, provided a seamless and collaborative care experience. “Our team-based model allows for better coordination and patient support,” said Clayton, who helped manage Pierce’s preoperative workup and performed her postop visit via telemedicine. “It was clear she wanted answers and a plan, and we were glad to be able to guide her through this process together.”

Zheng performed the adrenalectomy robotically, using a posterior approach — an advanced technique that involves going through the back instead of the front of the abdomen. “It’s a less common approach, but for the right patients, it can reduce pain and speed up recovery,” Zheng said.

Pierce said she felt calm going into the procedure. “Usually, I have white coat syndrome and feel anxious, but this time I didn’t. Everyone gave me step-by-step instructions, and Dr. Zheng explained everything clearly. I really felt like I was in good hands.”

Within a week or two of her June surgery, Pierce noticed changes. “I dropped four pounds almost immediately,” she said. “My face wasn’t as puffy. I felt less anxious and more like myself. Even though I was still recovering, I had more energy, and my body felt like it had reset.”

“Surgery to correct cortisol-producing tumors can make a major difference in quality of life, even if patients don’t meet the full criteria for a Cushing’s diagnosis,” Zheng said. “Mrs. Pierce’s case is a perfect example. She didn’t feel well, but she didn’t know why. Her endocrinologist saw [that] her metabolic parameters were getting worse. Now that the tumor is gone, her symptoms are improving, and her health trajectory is back on track.”

Just a month after surgery, Pierce says she has more energy and is continuing to lose weight. She’s relieved that a straightforward procedure made such a noticeable difference in how she feels.

From https://blogs.bcm.edu/2025/07/23/patient-finds-relief-after-adrenal-gland-tumor-removed/

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A Second Look at Cushing Disease: Hypercortisolism Recurrence From Another Gland

Posted on June 2, 2025 by MaryO

Abstract

Cushing disease (CD) is the most common form of adrenocorticotropin (ACTH)-dependent Cushing syndrome (CS), whereas unilateral adrenal adenoma is the most common cause of ACTH-independent CS. However, the occurrence of different subtypes of CS in a single individual is very rare.

We present a case of a 44-year-old woman with distant histories of left adrenalectomy for an adrenal adenoma and total thyroidectomy following the diagnosis of papillary thyroid carcinoma.

She was later diagnosed with CD, achieving disease remission after pituitary surgery, but subsequently developed adrenal CS from the remaining right adrenal gland. After discussing the potential advantages and drawbacks of another adrenalectomy to remove her right adrenal gland, the patient declined surgery and opted for medical management. After 7 years of imaging follow-up studies, her right adrenal adenoma has remained stable in size and she is biochemically controlled on low-dose osilodrostat therapy. Our case emphasizes the importance of recognizing the rare occurrence of successfully treated CD followed by the recurrence of CS from a different gland, and the adoption of management strategies tailored to each individual patient’s preferences.

Introduction

Cushing syndrome (CS) arising from either pituitary or adrenal lesions is generally a rare condition, with an estimated prevalence of 10 to 15 cases per million individuals [1]. The majority of cases of endogenous CS are adrenocorticotropin (ACTH) dependent, accounting for 80% to 85% of cases. Among these cases, approximately 75% to 80% are attributed to pituitary corticotroph adenomas [2, 3], whereas ACTH-independent CS constitutes 15% to 20% of cases, with 90% of such cases caused by unilateral adrenal adenomas [4]. Surgery is the preferred first-line treatment option for all cases of CS; however, approximately 20% cases may recur following surgical resection that necessitates second-line treatments, such as medical therapy, adrenalectomy, and radiation therapy [5, 6].

Bilateral adrenalectomy may be considered for some Cushing disease (CD) patients, such as patients with persistent or recurrent disease following pituitary surgery, medication intolerance, nonadherent or unresponsive to medical therapy, or in situations where rapid normalization of life-threatening hypercortisolism is required. However, this procedure carries the risk of development of Nelson syndrome and lifelong use of glucocorticoid and mineralocorticoid replacement therapies [7]. Consequently, the role of bilateral adrenalectomy in patients with CS still remains a subject of debate and medical therapy is increasingly preferred [8]. Additionally, there is accumulating evidence affirming the effectiveness, safety, and tolerability of medical therapies leading to its increased use in the treatment of CS, subsequently allowing a more personalized approach for these patients [9].

We hereby present a case of a patient with distant histories of left adrenalectomy for an adrenal adenoma and total thyroidectomy for papillary thyroid carcinoma, who later developed CD that required transsphenoidal resection. After 6 years of disease remission following her transsphenoidal resection, the patient sought medical guidance for recurrence of her hypercortisolemic symptoms leading to the discovery of a right cortisol-secreting adrenal adenoma and the subsequent diagnosis of adrenal CS.

Case Presentation

A 44-year-old African American woman presented to our clinic in 2017 for worsening headaches, joint and muscle pains, muscle weakness, facial acne, facial roundness, facial plethora, pink abdominal striae, easy skin bruising, hair loss, and weight gain of 7 kg over 6 months. Her past surgical history included a left adrenalectomy for an adrenal adenoma in 2009, transsphenoidal resection of a corticotroph adenoma in 2011, and total thyroidectomy for papillary thyroid carcinoma in 2016. The left adrenalectomy was undertaken due to worsening hypertension and mildly elevated plasma metanephrines and catecholamines; however, the pathology revealed an adrenal cortical adenoma and not pheochromocytoma characteristics, demonstrating clear and eosinophilic cytoplasm, low mitotic activity, no significant atypia, and no vascular invasion, while immunohistochemistry was positive for inhibin, calretinin, and Melan-A. Genetic studies, including multiple endocrine neoplasia (MEN) 1 testing, were performed and were negative. Her past medical history included long-standing type 2 diabetes mellitus, metabolic dysfunction–associated steatohepatitis, and osteoporosis with compression fractures on her lumbar 4 to 5 vertebral bodies of her spine. The patient reported no known family history of endocrine disorders.

Diagnostic Assessment

Further testing at this clinic visit revealed elevated 24-hour urine cortisol levels of 49.3 μg/24 hours (135.73 nmol/24 hours) (reference range [RR] <45 μg/24 hours; <124.40 nmol/24 hours), unsuppressed overnight 1-mg dexamethasone suppression test with a postdexamethasone cortisol level of 15.8 µg/dL (435.88 nmol/L) (RR <5 µg/dL; <138 nmol/L), a low dehydroepiandrosterone sulfate level of 14 µg/dL (0.38 µmol/L) (RR: 32-240 µg/dL; 0.86-6.49 µmol/L), and normal 24-hour urine metanephrine levels. These findings, in conjunction with the patient’s clinical symptoms, raised concerns of recurrence of CS, especially considering a recent magnetic resonance imaging scan that had revealed some residual tissue in the sella described as a nonenhancing cystic foci in the left lateral aspect of the pituitary gland (Fig. 1).

Nonenhancing cystic foci in the left lateral aspect of the pituitary gland (A: sagittal view; B: coronal view).

Figure 1.

Nonenhancing cystic foci in the left lateral aspect of the pituitary gland (A: sagittal view; B: coronal view).

Follow-up laboratory testing revealed plasma morning ACTH of less than .1 pg/mL (<23.98 pmol/L) (RR: 7-63 pg/mL; 152.6-1373.4 pmol/L), whereas 24-hour urinary free cortisol and serum morning cortisol levels were within the normal range at 47 mcg/24 hours (129.98 nmol/24 hours) and 14.8 mcg/dL (408.67 nmol/L) (RR <45 μg/24 hours; 124.40 nmol/24 hours). Due to the low plasma morning ACTH level, an abdominal magnetic resonance imaging scan was performed that revealed a right adrenal adenoma measuring 6.3 × 3.5 cm. Additionally, her insulin-like growth factor 1 was elevated at 316 ng/mL (41.28 nmol/L) (RR: 7.44-25.44 nmol/L), while her prolactin levels were normal. Based on her elevated insulin-like growth factor 1 level, an oral glucose tolerance test for growth hormone suppression was performed that ruled out acromegaly, with a nadir growth hormone level of 0.20 ng/mL (0.61 mIU/L) (RR <1 ng/mL; <3.03 mIU/L) [10].

Suspecting recurrence of CS, her serum cortisol and ACTH levels were closely monitored over the course of a year (Table 1). During this period, her 24-hour urinary free cortisol levels were either mildly elevated or within the normal range at 47, 39, and 32 mcg/24 hours (129.74, 107.63, and 88.14 nmol/day, respectively) (RR <45 μg/24 hours; <124.40 nmol/24 hours), prompting further evaluation with late-night salivary cortisol measurements on 4 separate occasions that were consistently elevated at 0.154, 0.218, 0.298, and 0.109 μg/dL (4.24, 6.01, 8.21, and 3.01 nmol/L, respectively) (RR: <0.010-0.090 μg/dL; <0.28-2.48 nmol/L). The persistent suppression of ACTH levels supported the diagnosis of adrenal CS, and an abdominal computed tomography (CT) scan revealed a lipid-rich adenoma that was stable in size measuring 6.6 × 3.5 cm (Fig. 2).

Abdominal computed tomography images demonstrating adrenal adenoma in the right adrenal gland measuring 6.6 × 3.5 cm.

Figure 2.

Abdominal computed tomography images demonstrating adrenal adenoma in the right adrenal gland measuring 6.6 × 3.5 cm.
Table 1.

Comparison of hormonal parameters over time

Hormone tested Initial consult Post adrenal adenoma findingsa Post osilodrostat (1 y)b Reference range
8 Am ACTH <1.1 pg/mL
(<0.24 pmol/L)		 <1.1 pg/mL
(<0.24 pmol/L)		 3.5 pg/mL
(0.76 pmol/L)		 7.2-63.3 pg/mL
(1.6-13.9 pmol/L)
8 Am serum cortisol 14.8 μg/dL
(408.67 nmol/L)		 16.3 μg/dL
(448.1 nmol/L)		 4.2 μg/dL
(115.8 nmol/L)		 6.2-19.4 μg/dL
(171.1-534.41 nmol/L)

Reported in conventional units (SI units).

Abbreviation: ACTH, adrenocorticotropin.

aOne year after initial consult.

bTwo years and 9 months after initial consult.

Treatment

Because our patient was biochemically in remission following her pituitary surgery for CD for 6 years before the current presentation and now has biochemical evidence of recurrence of hypercortisolism due to adrenal CS, treatment options were discussed with the patient, including medical therapy and right adrenalectomy. The patient opted against a right adrenalectomy due to concerns about the need for lifelong hydrocortisone and fludrocortisone, and decided to commence medical therapy. The patient was offered the option to start either ketoconazole or a glucocorticoid receptor antagonist (mifepristone). The patient declined being treated with ketoconazole and mifepristone, as she was concerned about the side-effect profile of liver function test derangements due to her history of metabolic dysfunction–associated steatohepatitis and hypokalemia, respectively. Hence, she decided to start osilodrostat therapy and began a low dose of 1 mg twice daily.

Outcome and Follow-up

Annual follow-up CT imaging studies of the patient’s adrenal gland for the next 7 years after the current presentation have shown stability in the size of her right adrenal adenoma. Her blood pressure is well controlled with a single antihypertensive medication (amlodipine), and her glycated hemoglobin has remained in the nondiabetic range. Additionally, she has been experiencing increased energy levels and improvement in peripheral edema. While on osilodrostat therapy, she continues to be biochemically well controlled and has had only a single episode of adrenal insufficiency. A chronological overview of clinical events is displayed in Fig. 3. Because her morning serum cortisol level was relatively low (5.6 µg/dL [154.5 nmol/L]), her osilodrostat dose was further decreased to 1 mg in the evening in December 2024 and she was educated on the proper timing and administration of rescue oral hydrocortisone therapy of 5 to 10 mg, as needed, whenever she developed symptoms of adrenal insufficiency.

Chronological overview of clinical events.

Figure 3.

Chronological overview of clinical events.

Discussion

While previous reports have documented the coexistence of CD with a solitary adrenal adenoma [9], the unique aspect of our case lies in the development of a right adrenal adenoma after a distant history of surgical resection of a left adrenal adenoma and the achievement of disease remission following transsphenoidal resection of a pituitary corticotroph adenoma [4]. Several molecular studies have been performed to elucidate the pathogenesis of recurrent and refractory endocrine tumors, revealing links to genetic factors. The majority of previously reported cases of pituitary adenomas coexisting with adrenal adenoma are seen in patients with MEN syndromes [11]. The genetic testing for MEN 1 syndrome conducted on our patient yielded negative results. However, while MEN 1 was ruled out in our patient, it is possible that other, yet-unidentified genetic factors may contribute to this pattern of tumor formation, including Carney complex and McCune-Albright syndrome, that can be associated with adrenal adenomas and will need to be tested in our patient. Notably, our patient does not report any family history of endocrine tumor syndromes, and corticotroph adenomas are primarily sporadic monoclonal neoplasms that are rarely found in genetic syndromes [12].

In assessing our patient, we also noted a discrepancy between the overt cushingoid features in our patient and the marginal elevations in 24-hour urine free cortisol levels, underscoring the complexities in diagnosing and characterizing the severity of hypercortisolemic states. While 24-hour urine free cortisol remains an important screening test, its limitations must be acknowledged, including variability in 24-hour cortisol secretion, renal clearance differences, and the potential for episodic hypercortisolism that may not be fully captured in a single 24-hour urine collection measurement [13]. These factors have been substantiated by Petersenn et al [14], who reported significant intrapatient variability in 24-hour urinary free cortisol measurements, with a coefficient of variation of approximately 50%, highlighting the need for multiple sample collections to improve the reliability of assessments. These fluctuations, along with individual differences in cortisol sensitivity and metabolism, may account for the presence of varying phenotypic features that are not correlated with the degree of urinary hypercortisolism [15]. In our patient’s case, her clinical phenotype, imaging data, and the associated comorbidities are more useful in assessing the severity of CS, highlighting the importance of thorough and comprehensive clinical and biochemical assessments for CS patients.

Another aspect contributing to the complexity of our case included the treatment options that we could offer to our patient. She opted to avoid a second adrenalectomy, which has the potential of causing Nelson syndrome [9]. Initially, we offered the patient to start treatment with a steroidogenesis inhibitor such as ketoconazole, which has been used to treat hypercortisolism for more than 30 years with an average remission rate of 71.1% [9]. Another alternative was mifepristone, a glucocorticoid receptor antagonist used in the treatment of hyperglycemic patients with underlying CS [16]. However, our patient decided against being treated with ketoconazole and mifepristone due to the side-effect profiles of liver function test derangements and hypokalemia, respectively. Hence, she was offered osilodrostat treatment, to which she has responded well symptomatically, and her disease currently remains well-controlled in remission.

Because of the effectiveness of osilodrostat, adrenal insufficiency is a side effect that was commonly reported in previous pivotal clinical trials [17, 18]. More recently there have been several publications describing prolonged duration of adrenal insufficiency even after osilodrostat discontinuation that requires close monitoring, a finding that remains mechanistically unclear, especially with its short half-life of approximately 4 hours [19, 20]. Given the emerging reports of prolonged adrenal insufficiency after osilodrostat discontinuation [19, 20], close monitoring of serum cortisol levels and patient education to manage symptoms of adrenal insufficiency are essential for the long-term management of patients on osilodrostat therapy. Finally, eventual recovery of adrenal function has also been recently reported [21], hence clinicians are advised to exercise a low threshold of retesting the adrenal reserve of patients who have discontinued osilodrostat therapy.

Learning Points

  • This case highlights an unusual scenario in which a patient with CS presented with both adrenal and pituitary adenomas following prior surgical resections. Physicians should be aware of the rare occurrence of two different etiologies of CS in the same patient and should consider its possibility in patients with recurrent hypercortisolism.
  • The patient’s hesitation to undergo a second adrenalectomy demonstrates the importance of personalized medicine in individualizing the treatment plan for our patient.
  • Recent reports suggest that prolonged adrenal insufficiency after discontinuation of osilodrostat and the eventual recovery of adrenal function can occur in some patients. Clinicians should be aware of this and ensure close monitoring of adrenal function after discontinuing therapy.

Contributors

All authors made individual contributions to authorship. K.C.J.Y. was involved in the diagnosis and management of this case, manuscript review, and text editing. M.M.-G. was involved in manuscript preparation, writing, and submission. Both authors reviewed and approved the final draft.

Funding

This research did not receive any specific grants from any funding agencies in the public, commercial, or not-for-profit sectors.

Disclosures

None.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the present study.

From https://academic.oup.com/jcemcr/article/3/6/luaf089/8117205?login=false

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