SAT-463 Cyclic Cushing’s Syndrome: A Case Report and Review of Diagnostic Challenges

The cyclic Cushing's syndrome is a rare disease characterized by multiple episodes of elevated cortisol levels alternating with periods of its normal secretion. The so-called hypercorticism cycles may be either regular or episodic with intercycle intervals as long as a few days to several years. Most researchers agree that the reliable diagnosis of cyclic Cushing's syndrome should be based on laboratory detection of 3 peaks and 2 falls of plasma cortisol level. Cyclic Cushing's syndrome may be either ACTH dependent or independent. A review of 65 verified cases indicates that this condition may be caused by pituitary corticotropinoma (54%), ectopic ACTH-producing tumour (26%), and adrenal tumour (roughly 11%). The cause of the disease remains uncertain in 9% of the patients. Pathophysiological mechanisms of cyclic Cushing's syndrome are poorly known. In certain cases of bilateral macronodular adrenal hyperplasia or adrenal corticosteroma, it may be associated with the presence of ectopic receptors or anomalous expression of normally located receptors. The majority of the patients presenting with cyclic Cushing's syndrome exhibit symptoms of classical hypercorticism that manifest themselves either on a permanent or cyclic basis. In a small number of patients, clinical signs of cyclic Cushing's syndrome are virtually absent. Variations of the clinical picture and conflicting results of hormonal assays taken together make cyclic Cushing's syndrome difficult to diagnose. Therefore, physicians must be aware of this condition and actively search for it in all patients believed to have an enhanced cortisol production despite normal results of laboratory analysis. Frequent changes of urinary or salivary free cortisol levels are reliable and convenient criteria for cyclic Cushing's syndrome in patients suspected to have this condition. Results of cortisol stimulation or suppression tests are likely to lead to a false conclusion due to spontaneous falls and rises in serum cortisol levels at the time of analysis. Given laboratory confirmation of cyclic Cushing's syndrome, subsequent studies should be focused on the elucidation of its cause. The average life expectancy of patients with cyclic Cushing's syndrome remains to be determined.

Introduction Silent corticotroph adenomas (pituitary neuroendocrine tumours (PitNET)) are a rare subset of nonfunctioning adenomas. The higher aggressiveness in terms of invasion and recurrence make these tumors dangerous and close follow-up in experienced centers is recommended. Clinical Case A 21-year-old obeseo (Body Mass Index:31.71) male patient unable to lose weight and complaining of headaches was referred to the Department of Neurosurgery for a pituitary macroadenoma. He had previously used liraglutide treatment Many purple striae were also seen on the body of the patient, who stated that his wounds did not heal easily. Visual acuity and visual field were normal. There was no neurodeficiency. Endocrinological evaluation revealed that the tumor was nonfunctioning (Table 1). Magnetic resonance imaging of the pituitary gland showed a mass lesion in the right side of the pituitary gland extending to the suprasellar and parasellar area (Knosp grade II) (Fig.1). The tumor with soft consistency was totally removed by endoscopic binostril transsphenoidal approach. The postoperative cortisol was 11.53 µg/dl (6.02-18.4) and free T4 was 1.32 ng/dL (0.93-1.7). The patient had a transient diabetes insipidus in the postoperative course, and he was discharged on the 4th day after surgery. Pathological examination revealed a pituitary adenoma immunostaining diffusely with ACTH, other hormones were unexpressed. Ki-67 was %2. Histological invasion of the dura was noted. Although the patient was clinically overweight and had purple striae suggestive of Cushing's syndrome (CS), his cortisol and ACTH levels were normal and suppressible with 1 mg dexamethasone suppression test. However, his tumour tissue showed diffuse ACTH expression, which led to the diagnosis of a silent ACTH adenoma. Since the clinical findings were not completely silent, could we assume that he suffered from cyclic CS? Cyclic (intermittent or periodic) CS is a condition characterised by alternating periods of transiently elevated cortisol levels followed by normal to reduced levels. The diagnosis of cyclic CS requires the presence of at least three confirmed episodes of elevated cortisol levels interspersed with two periods of normal cortisol levels. As we know, the cortisol secretion cycle is unpredictable and laboratory tests during the normal cortisol secretion period of the cyclic CS often show negative results as in our patient. Conclusion Postoperative follow-up of a silent corticotroph PitNET and cyclic CS patient, both of whom require close and life-long monitoring.Figure 1.Magnetic resonance imaging of the pituitary gland; coronal sections T1- weighted (a), T2-weighted (b), sagittal (c), and coronal (d) sections with T1 contrast enhancement. The mass lesion on the right side of the pituitary gland extending superiorly to the right internal carotid artery contains a hemorrhagic fluid component with heterogeneous contrast enhancement, is 16*12*9 mm in size, and corresponds to a hemorrhagic pituitary macroadenoma. Table 1.Hormonal values at presentationACTH, adrenocorticotropic hormone; DST, dexamethasone suppression test; fT4, free thyroxine; IGF-1, insulin-like growth factor 1; PRL, prolactin; TSH, thyroid-stimulating hormone.

Diagnostic challenges in cyclic Cushing's syndrome: a systematic review

Measurement of cortisol in 24-h urine collections and midnight saliva are standard screening tests for Cushing's syndrome (CS). These tests reflect cortisol levels during a maximum of 24 h and do not provide historical information. Therefore, they can yield normal results in case of cyclic CS, which is a rare disorder that is characterized by alternating episodes of endogenous cortisol excess and normal cortisol secretion. The measurement of cortisol in scalp hair is a novel tool that might be helpful to establish the diagnosis of (cyclic) CS. Our aim was to study whether hair cortisol timelines correspond with clinical course in patients with CS and whether we could create retrospective timelines of cortisol exposure that correspond with symptomatic periods in patients suspected of cyclic CS. Scalp hair was collected in 14 patients with confirmed CS and six patients suspected of cyclic CS. Cortisol was extracted from the hair samples with methanol, and an ELISA was used to measure cortisol levels in hair extracts. A group of 96 nonobese individuals were used as a control group. Hair cortisol levels were significantly elevated in CS patients (P<0.0001). Sensitivity and specificity of hair cortisol measurements for CS were 86 and 98%, respectively. Hair cortisol timelines of patients with CS and cyclic CS corresponded with clinical course. Hair samples can provide a historical timeline that corresponds with clinical course in patients with (cyclic) CS. This new diagnostic tool can contribute significantly to early recognition of patients suffering from cyclic CS.

Cushing's syndrome results from chronic exposure to excessive circulating levels of glucocorticoids. To confirm the clinical suspicion, biochemical tests are needed. These biochemical tests include the measurement of excess total endogenous cortisol secretion assessed by 24-hour urinary free cortisol (UFC), loss of the normal feedback of the hypothalamo-pituitary-adrenal axis assessed by suppressibility after dexamethasone testing, and disturbance of the normal circadian rhythm of cortisol secretion assessed by midnight serum or salivary cortisol. We searched the Medline, Pubmed, journal articles, WHO publications and reputable textbooks relating to Cushing's syndrome using publications from 1995 to 2011. UFC has been the classic screening test used to confirm hypercortisolemia as the first step in diagnostic work-up of Cushing's syndrome. Its long-term use in clinical practice has led to emergence of significant evidence regarding the utility of UFC in the diagnosis of Cushing's syndrome. UFC would have been a simple diagnostic tool to use but for the drawbacks in the sample collection, different laboratory methods of assay, not easily determined normal range. UFC use as a screening test is not strongly favoured because cortisol is not uniformly secreted during the day, and the increased prevalence of mild, preclinical or cyclic Cushing's syndrome. A very high level of UFC negates the need for other test procedures in patients with obvious symptoms and signs of Cushing's syndrome. We therefore suggest that UFC should be used with other screening tests for Cushing's syndrome to increase diagnostic yield.

Disclosure: K. Manglani: None. S.T. Sharma: None. Pregnancy-induced hypercortisolism is a rare phenomenon with very few cases reported in the literature. The pathogenesis is thought to be secondary to the expression of aberrant LH/hCG receptors on the adrenal gland that stimulate cortisol production in pregnancy. We present a case of a 31-year-old female with no past comorbidities until her first pregnancy in 2017 when she gained around 50lbs, developed violaceous striae, acne, hirsutism, depression with suicidal ideation for which she was hospitalized twice, and underwent emergent C-section at 34 weeks’ gestation due to pre-eclampsia. She was referred to the Endocrinology clinic post-delivery, and screening for Cushing syndrome was negative at that time: 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC) and 1-mg dexamethasone (dex) suppression test (DST) were normal. She presented again in 2020 during her second pregnancy at 14 weeks gestation, with 20lb weight gain in the first trimester, acne, hirsutism, and easy bruising. Labs showed cortisol of 22.4 mcg/dL (6.2-19.4), ACTH &amp;lt;1.5 pg/mL, total testosterone 168 ng/dL (8-48), androstenedione 751 ng/dL (41-262), DHEAS 91.2 mcg/dL (84.8-378), 24-hour UFC 277 mcg/day (6-42), LNSC 0.671 mcg/dL, 1mg DST with post-dex cortisol 24 mcg/dL (dex level 58 ng/dL), and 8-mg DST with post-dex cortisol level of 28.2 mcg/dL (dex level 457 ng/dL). Testing was consistent with ACTH-independent Cushing syndrome. Ultrasound and MRI of the abdomen/pelvis showed normal adrenal glands with no hyperplasia or mass. Given worsening hypercortisolism and her course during a prior pregnancy, medical treatment with metyrapone was initiated. We started at a dose of 500 mg daily and gradually increased to 1500 mg with close monitoring of her blood pressure and cortisol levels. She underwent vaginal delivery at 38 weeks’ gestation, and the baby required a brief stay in the NICU for respiratory distress but was otherwise doing well. The patient developed secondary adrenal insufficiency post-delivery requiring hydrocortisone, with recovery of her HPA axis in around 10 weeks. Since then, she has been off hydrocortisone with normal UFC, ACTH, and cortisol levels. This case enables discussion regarding the underlying etiology, diagnostic difficulties, and management of this rare condition. Although the exact etiology is unknown, the postulated mechanism is aberrant LH/hCG receptor expression given the patient’s presentation during each pregnancy, normal cortisol levels between both pregnancies, and a brief period of adrenal insufficiency post-delivery. Management of hypercortisolism during pregnancy remains challenging. Metyrapone, a steroidogenesis inhibitor, can be considered for control of hypercortisolemia during pregnancy (off-label) in select cases to prevent maternal and fetal complications. Presentation: 6/1/2024

The difficult diagnosis of cyclical Cushing’s syndrome Cyclic Cushing Syndrome (CCS) is a condition characterized episodes of normo- or hypocortisolism and episodes of hypercortisolism. The clinical presentation and complications are similar to non-cyclic CS. However, diagnosis is even more challenging than in non-cyclic Cushing's; various diagnostic modalities can yield both false positive and false negative results when testing is performed during an episode without hypercortisolism. Diagnostic tests for CS include 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), and the dexamethasone suppression test (DST). Unlike non-cyclic CS, DST can result in a paradoxical reaction. Repeated tests are needed when CCS is suspected, with testing conducted during periods of hypercortisolism. A new, promising technique for detecting CCS involves hair cortisol measurement, where cortisol levels can be determined over an extended period of time. However, there are currently no standardized reference values available. The underlying etiology of CCS is similar to that of classic CS, including ACTH-dependent hypercortisolism due to a pituitary adenoma or ectopic ACTH- or CRH production, and ACTH independent hypercortisolism. Further differentiation is based on various tests: dynamic testing (CRH, desmopressin, high-dose DST), bilateral inferior petrosal sinus sampling (BIPSS), and imaging (pituitary MRI, FDG-PET, somatostatin analogs PET-CT). The main difference from non-cyclic CS is that testing with desmopressin and BIPSS is unreliable when performed during a trough phase. The high-dose dexamethasone test can result in a paradoxical response. There is no clarity on the ideal sequence of investigations. In some cases, despite extensive investigations, the underlying etiology remains unclear.

We have studied a 57-yr-old woman with cyclic Cushing's syndrome of apparent pituitary origin who had a predominant cycle of 2-6 days. The patient also demonstrated an abnormal circadian rhythm, with afternoon peaks of plasma ACTH and plasma cortisol. In addition to these abnormal biorhythms, Fourier analysis showed what appeared to be a separate 35-day cycle. After 35 days of consecutive urinary free cortisol measurement, the patient was given cyproheptadine. During therapy with this agent, the urinary free cortisol levels fell dramatically, but cyclic secretion continued, albeit with a diminished amplitude. During general anesthesia for a bilateral adrenalectomy, there was a striking increase in the plasma ACTH level, and the ACTH concentration remained high in both the immediate and late postoperative periods. These observations indicated that stress could overcome cyclic ACTH secretion and that cortisol exerted feedback suppression on ACTH secretion. Although this is the predictable response for classic pituitary-dependent Cushing's syndrome, it is of interest in cyclic Cushing's syndrome, since previous studies of this entity have implied that cortisol secretion is independent of stimulation or feedback.

Cyclic Cushing's syndrome (CS) involves rhythmic fluctuations in ACTH secretion resulting in a cyclic variation of adrenal steroid production. In the majority of cases, cyclic CS is caused by an ACTH-secreting pituitary adenoma, but it can also be due to ectopic ACTH production or an adrenal adenoma. This condition should be strongly suspected in patients with symptoms or signs of hypercortisolism but normal cortisol levels and paradoxical responses to the dexamethasone test, that may reflect an increasing or decreasing endogenous hormone activity. Dynamic tests are best interpreted if they are performed during a sustained period of hypercortisolism. Sometimes, it is necessary to confirm the diagnosis over lengthy periods of observation. Responses to treatment must be closely monitored, interpreted and evaluated with caution because of the potential variations in steroidogenesis. An original case report of a cyclic Cushing's syndrome is presented in this review.

Background: Cushing's syndrome (CS) is associated with hypertension in approximately 80% of cases, which contributes to the increased mortality risk. Few cases of intermittent hypertension due to cyclic CS(CCS) have been reported. Case presentation: A 66-year-old woman with no specific medical history was referred to our hospital for evaluation of hypertension and leg edema. The Cardiovascular examination showed no abnormality in her cardiac function. Laboratory findings revealed hypokalemia, hyperglycemia, and metabolic alkalosis. She was tentatively initiated on calcium channel blocker (CCB) and insulin therapy. The endocrine examination revealed elevated ACTH and cortisol without circadian variation, which responded to neither the 8 mg dexamethasone suppression test nor CRH stimulation, leading to the diagnosis of ACTH-dependent CS. CT, FDG/PET CT, and Octreotide scan showed no obvious lesion other than bilateral adrenal enlargement. Enhanced MRI showed a normal pituitary gland with neither adenoma nor pituitary stalk deviation/tilt. Since the etiology of CS was not confirmed, metyrapone administration was initiated as symptomatic treatment. Her serum ACTH and cortisol fell rapidly after the initiation of metyrapone, and her blood pressure (BP) and blood glucose levels improved accordingly, even without the use of CCB and insulin. Since both ACTH and cortisol became normalized after discharge, metyrapone was tapered off after 4 months. Furthermore, CT showed normalization of the adrenal enlargement. For the next two months, her ACTH and cortisol remained within the normal limits, and her BP, serum potassium and blood glucose were well controlled. However, she visited our hospital because of re-elevated BP thereafter and was found to have re-elevated ACTH and cortisol with bilateral adrenal enlargement as well as re-decreased serum potassium. Since her BP and serum potassium levels were not controlled well even after she resumed taking metyrapone, the dose of metyrapone was increased, spironolactone was added, and CCB was resumed. Another two months later, her ACTH and cortisol normalized without metyrapone again, and her BP was well-controlled accordingly. This cyclical course of ACTH/cortisol elevation strongly suggested CCS. Conclusion: CCS is a clinical syndrome that exhibits a periodic or irregular increasing pattern in cortisol, which is a rare type of CS. Confirmation of CCS diagnosis is only possible during periods of relapse. In the present case, elevated BP was an indicator of hormonal fluctuations that could be appropriately treated. We report here a case of CCS that was diagnosed because of a good correlation between BP and hormone levels.

Pitfalls in the diagnosis and differential diagnosis of <scp>C</scp>ushing's syndrome

Disclosure: R. Desai: None. F. Sidra: None. S. Mirfakhraee: None. J. Liwei: None. P. Polanco: None. S. Al Mutar: None. O. Hamidi: None.Background: Cyclic Cushing syndrome (CS) secondary to ectopic adrenocorticotrophic hormone (ACTH) from an appendiceal carcinoid is extremely rare with only a few published cases thus far. This is the first reported case of a patient with extensive metastatic disease on initial presentation. Clinical Case: A 24-year-old woman with no past medical history was referred to endocrinology after developing 60lb weight gain, acne, fatigue, heat intolerance, lower extremity swelling, palpitations, and anxiety over a 3-month period with secondary amenorrhea 6 months prior to presentation. Family history was significant for bronchial carcinoid in her mother. Physical exam was notable for moon facies, wide purple striae on abdomen, hirsutism, dorsocervical and supraclavicular fat pads. Laboratory workup showed hypokalemia (3.2 mmol/L, n = 3.5-5.3), elevated urine free cortisol (UFC) (473 mcg/24hours, n<50), normal ACTH (16 pg/mL, n = 6-50), normal AM Cortisol level (15.3 mcg/dL, n=5-22) and abnormal 1-mg dexamethasone suppression with cortisol 8.8 mcg/dL (n≤1.8). Repeat UFC two weeks later was still elevated (539 mcg/24 hours). Evaluation with CT abdomen and pelvis revealed a 3 cm enhancing appendiceal mass, enlarged periappendiceal mesenteric lymph nodes, and a 4 cm enhancing right hepatic lobe lesion. Further imaging with Ga-68 Dotatate PET/CT confirmed increased radiotracer uptake in the appendiceal mass, lymph nodes, hepatic mass, and right breast. The patient underwent liver biopsy and pathology showed well different neuroendocrine tumor (NET) grade 1 and positive ACTH stain. Genetic testing was negative. She was unable to tolerate ketoconazole and was initially treated with lanreotide 120mg every 4 weeks. Repeat biochemical testing one month after initiation of lanreotide showed elevated UFC (65mcg/24hrs), elevated ACTH (52 pg/mL) and elevated serum cortisol (36.2mcg/dL). Two weeks later ACTH decreased to 14 pg/mL and serum cortisol was <1 mcg/dL which was concerning for severe cyclic ectopic CS secondary to metastatic NET. She was managed with early bilateral adrenalectomy given severe cyclic CS with extensive tumor burden in a young female hoping to preserve fertility. The pathology of her right adrenal gland was notable for metastatic well differentiated neuroendocrine carcinoma. She was subsequently started on physiologic steroids and underwent extensive debulking surgery. 1.5 years later she had progression of disease requiring initiation of peptide receptor radionuclide therapy (PRRT) but has since been in remission. Conclusion: This case demonstrates the importance of individualized medical management of patients with ectopic ACTH syndrome and highlights the need for consideration of early bilateral adrenalectomy for patients with severe CS and metastatic disease.Presentation: Monday, July 14, 2025

Cyclic cushing's syndrome

A 39-year-old man was referred to an endocrinology clinic for evaluation of his Cushing syndrome. He had gained 20 kg over 5 years and complained of intermittent headaches and easy bruisability. His medical history included a left foot fracture associated with minimal trauma 2 years earlier, hypertension, and stable Crohn disease with no use of exogenous glucocorticoids for at least 10 years. Measurements of plasma adrenocorticotropic hormone, 24 h urine free cortisol excretion, late-night salivary cortisol, serum cortisol levels before and after corticotropin-releasing hormone administration during a dexamethasone suppression/corticotropin-releasing hormone-stimulation test, pituitary MRI, and inferior petrosal sinus sampling. Cyclic Cushing syndrome secondary to an ectopic pituitary adenoma. The cyclic nature of Cushing syndrome was suggested by the absence of hypercortisolemia during inferior petrosal sinus sampling, and was confirmed by multiple 24 h urine free cortisol measurements. The patient underwent transsphenoidal surgery, during which a 5 mm firm, round, midline sphenoid sinus lesion was identified and resected. In preoperative imaging studies, this lesion had been interpreted as being a mucosal polyp. At microscopic examination, the lesion was found to be a pituitary adenoma, which stained diffusely with antiadrenocorticotropic-hormone antibodies. Explorations of the sella and pituitary did not reveal any abnormalities. Postoperatively, the patient became hypocortisolemic and his cushingoid features resolved. His adrenal function normalized 3 months after surgery. At 18 months, the patient continued to be symptom-free with normal levels of urinary-free cortisol and midnight salivary cortisol.

Diagnosing Cushing's syndrome is challenging and is further hampered when investigations are performed in a patient with cyclic Cushing's syndrome. A subset of patients with Cushing's syndrome exhibit periods of abnormal cortisol secretion with interspersed normal secretion. Patients can have periods of clinical improvement during these quiescent phases or remain symptomatic. Initial diagnostic testing can be challenging because of the unpredictable durations of the peak and trough phases, and it is especially challenging when the diagnosis of cyclic Cushing's syndrome has not yet been determined. Here, the authors present the case of a patient with Cushing's disease with a pathology-proven adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma and whose initial inferior petrosal sinus sampling (IPSS) results were deemed indeterminate; further studies elucidated the diagnosis of cyclic Cushing's syndrome. Repeat IPSS was diagnostic of a central source for ACTH secretion, and the patient was treated successfully with transsphenoidal resection. Literature concerning the diagnosis and management of cyclic Cushing's syndrome is also reviewed.