Relapse of Cyclic Cushing Syndrome With a 19-Year Remission: Potential Involvement of COVID-19 in the Relapse

Abstract

Cyclic Cushing syndrome (cyclic CS) is characterized by phases of hypercortisolemia and normocortisolemia or hypocortisolemia. Here, we present the first case of cyclic CS with a relapse following COVID-19 infection and a long-term normocortisolemic phase of 19 years. The patient developed CS at the age of 30. The first remission of CS was achieved by the use of steroidogenesis inhibitors and was eventually maintained without the use for 19 years. At the age of 49, the patient suffered from COVID-19 infection and was treated with glucocorticoids, after which the patient developed CS relapse. Intriguingly, the second remission was induced by steroidogenesis inhibitors. Therefore, the cyclic CS in the present case could be dependent on a glucocorticoid-driven positive feedback mechanism. Although the diagnostic tests for CS suggested Cushing disease, no pituitary tumors were detected. However, radionuclide scanning revealed a thymic tumor. Partial thymectomy resulted in the third remission. The patient was eventually diagnosed with ACTH-secreting thymic typical carcinoid tumors. The present case suggests that careful follow-up is essential for patients with uncured cyclic CS even if long-term remission is achieved. Additionally, a relapse of cyclic CS with a glucocorticoid-driven positive feedback mechanism could be induced by infection and treatment with glucocorticoids.

Introduction

Cyclic Cushing syndrome (cyclic CS) is a subtype of CS characterized by recurrent phases of hypercortisolemia (peaks) and normo- or hypocortisolemia (troughs). Recent studies suggest that this phenomenon is more common than previously believed and occurs in 14% to 18% of CS cases [1]. Cushing disease (CD) is the most common cause of cyclic CS and accounts for more than 50% of cases. The other types of cyclic CS are ectopic and adrenocorticotropic hormone (ACTH)-independent CS [1]. Cycle lengths can vary widely, from a few days to many years, with intervals that are often irregular and unpredictable [1]. This cyclic nature can interfere with the results of diagnostic tests, making diagnosis and treatment difficult [1, 2]. Although the exact mechanisms underlying this cyclicity are unclear, a glucocorticoid-driven positive feedback loop has been suggested as one possible mechanism in ACTH-dependent CS [3, 4]. Remission due to a decrease in glucocorticoid levels caused by steroidogenesis inhibitors has been reported, whereas relapse caused by exogeneous glucocorticoids has also been reported [3, 5]. Moreover, ex vivo experiments using resected CD tumors revealed an increase in ACTH levels in the media after dexamethasone treatment [4].

Herein, we present a rare case of ACTH-dependent cyclic CS that relapsed after significant long-term remission for 19 years. Interestingly, relapse can be triggered by COVID-19 infection and glucocorticoid treatment for COVID-19 through a glucocorticoid-driven positive feedback mechanism.

Case Presentation

A 30-year-old man presented with increased appetite, weight gain, and abdominal striae. He was diagnosed with ACTH-dependent CS based on cushingoid features and elevated plasma ACTH (93.3 pg/mL [SI: 20.5 pmol/L]; reference range [ref] 7-63 pg/mL [SI: 1.5-13.9 pmol/L]) and serum cortisol levels (34.6 μg/dL [SI: 954.5 nmol/L]; ref 4.0-18.3 μg/dL [SI: 110.3-504.8 nmol/L]) (Table 1). He was initially treated for 3 months with trilostane, a 3β-hydroxysteroid dehydrogenase inhibitor approved for human use in Japan, followed by 1 month of mitotane. Both were discontinued due to side effects. He was subsequently referred to our hospital for further evaluation and treatment. However, the plasma ACTH and serum cortisol levels of the patient improved to within reference ranges (58 pg/mL [SI: 12.8 pmol/L] and 7.1 μg/dL [SI: 195.9 nmol/L], respectively), despite no specific treatment, suggesting spontaneous remission occurred. Further investigation revealed remission of CS. His follow-up monitoring was stopped at the age of 37 because his remission had continued. No abnormalities were revealed during annual medical checkups until the age of 44.

Table 1.

Hormone concentrations in the present patient at the onset and at the time of relapse

	At the onset	At the time of relapse	Reference range
ACTH	93.3 pg/mL [20. 5 pmol/L]	165 pg/mL [36.3 pmol/L]	7-63 pg/mL [1.5-13.9 pmol/L]
Cortisol	34.6 μg/dL [954.5 nmol/L]	40.6 μg/dL [1120.2 nmol/L]	4.0-18.3 μg/dL [110.3-504.8 nmol/L]
24-h UFC	Not measured	314 μg/day [866.2 nmol/day]	5.5-66.7 μg/day [15.2-184.0 nmol/day]

Abbreviations: ACTH, adrenocorticotropic hormone; 24-h UFC, 24-hour urinary free cortisol.

At the age of 49, he was infected with COVID-19 and received 1 month of glucocorticoid treatment. This regimen included methylprednisolone at a dosage of 2 g/day for the initial 2 days, followed by 1 g/day for the next 2 days. Subsequently, the prednisolone dosage was gradually tapered from 20 mg/day over a month. Afterward, he experienced general fatigue, increased appetite, moon face, and 11 kg of weight gain within 2 months. Elevated plasma ACTH and serum cortisol levels led to his admission to our hospital for the second time in 19 years.

Diagnostic Assessment

Upon admission, his height, body weight, and body mass index were 166.2 cm, 76.6 kg, and 27.7 kg/m², respectively. His blood pressure was 270/140 mmHg without medication. He exhibited characteristic cushingoid features, including moon face, buffalo hump, central obesity, abdominal striae, and bruising. The laboratory findings revealed elevated plasma ACTH levels (165 pg/mL [SI: 36.3 pmol/L]), hypercortisolism (serum cortisol: 40.6 μg/dL [SI: 1120.2 nmol/L], 24-h urinary free cortisol: 314 μg/day [SI: 866.2 nmol/day]; ref 5.5-66.7 μg/day [SI: 15.2-184.0 nmol/day]) (Table 1), lymphopenia (lymphocyte count: 545/μL), hypokalemia (serum potassium: 2.2 mEq/L [SI: 2.2 mmol/L]; ref 3.6-4.8 mEq/L [SI: 3.6-4.8 mmol/L]), hyperglycemia (casual plasma glucose: 549 mg/dL [SI: 30.5 mmol/L], glycated hemoglobin A1c: 8.2% [ref 4.6%-6.2%]), and renal insufficiency (serum creatinine: 2.44 mg/dL [SI: 215.7 μmol/L]; ref 0.6-1.2 mg/dL [SI: 53.0-106.1 μmol/L], estimated glomerular filtration rate: 23.9 mL/min/1.73 m²). A relapse of ACTH-dependent cyclic CS was diagnosed based on his 19-year medical history. Owing to the high risk of infection, metyrapone was initiated to improve hypercortisolemia prior to diagnostic tests. As shown in Fig. 1, both the plasma ACTH and serum cortisol levels decreased after metyrapone treatment. Diagnostic tests were performed in accordance with the Japanese diagnostic criteria for CD 5 days during metyrapone cessation (Table 2). Late-night serum cortisol levels were elevated and exceeded 5.0 μg/dL [SI: 138.0 nmol/L]. Incomplete suppression of serum cortisol levels was noted in a low-dose overnight dexamethasone suppression test (DST). Both the desmopressin and human corticotropin-releasing hormone (CRH) stimulation tests revealed significant responses in plasma ACTH levels. Additionally, his serum cortisol levels were suppressed by a high-dose DST. These results suggested CD rather than ectopic CS. Metyrapone treatment was resumed after diagnostic tests because of a risk of hypercortisolemia and maintained normocortisolemia. Since magnetic resonance imaging did not detect any pituitary tumors, selective cavernous sinus sampling with metyrapone cessation was performed a month after the diagnostic tests (Table 2). The results indicated a high central-to-peripheral ACTH gradient after CRH stimulation. Throughout diagnostic tests and cavernous sinus sampling, his plasma ACTH and serum cortisol levels remained within reference ranges despite metyrapone cessation (Table 2), suggesting that he was in a trough phase of cyclic CS. Consequently, these test results might be unreliable. After completing these diagnostic tests, metyrapone was resumed with replacement therapy (2000 mg of metyrapone and 20 mg of hydrocortisone). A computed tomography scan of the chest and abdomen revealed an 8-mm tumor in the anterior mediastinum. Additionally, both ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography and somatostatin receptor scintigraphy (¹¹¹In-pentetreotide) demonstrated focal radionuclide uptake in the tumor (Fig. 2). Therefore, the tumor in the anterior mediastinum was suspected to be an ectopic ACTH-secreting tumor.

Figure 1.

The time course of plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels after hospitalization. Blood samples were collected early in the morning before the administration of medications. Metyrapone was ceased on day 23 for subsequent diagnostic tests.

Table 2.

Diagnostic test results of Cushing syndrome in the present patient

	Early morning	Late night	Low-dose DST	High-dose DST
ACTH	53 pg/mL [11.7 pmol/L]	27 pg/mL [5.9 pmol/L]	23 pg/mL [5.1 pmol/L]	6 pg/mL [1.3 pmol/L]
Cortisol	12.6 μg/dL [347.6 nmol/L]	9.4 μg/dL [259.3 nmol/L]	5.0 μg/dL [137.9 nmol/L]	3.6 μg/dL [99.3 nmol/L]
Desmopressin test	0 min	15 min	30 min	60 min	90 min	120 min
ACTH	31 pg/mL [6.8 pmol/L]	89 pg/mL [19.6 pmol/L]	75 pg/mL [16.5 pmol/L]	52 pg/mL [11.5 pmol/L]	45 pg/mL [9.9 pmol/L]	39 pg/mL [8.6 pmol/L]
Cortisol	10.6 μg/dL [292.4 nmol/L]	24.3 μg/dL [670.3 nmol/L]	24.6 μg/dL [678.6 nmol/L]	19.4 μg/dL [535.2 nmol/L]	16.7 μg/dL [460.7 nmol/L]	15.0 μg/dL [413.8 nmol/L]
CRH stimulation test	0 min	15 min	30 min	60 min	90 min	120 min
ACTH	45 pg/mL [9.9 pmol/L]	143 pg/mL [31.5 pmol/L]	141 pg/mL [31.1 pmol/L]	81 pg/mL [17.8 pmol/L]	56 pg/mL [12.3 pmol/L]	42 pg/mL [9.2 pmol/L]
Cortisol	11.2 μg/dL [309.0 nmol/L]	22.9 μg/dL [631.7 nmol/L]	27.5 μg/dL [758.6 nmol/L]	22.6 μg/dL [623.4 nmol/L]	18.3 μg/dL [504.8 nmol/L]	14.7 μg/dL [405.5 nmol/L]
Cavernous sinus sampling		0 min	2 min	5 min	10 min	15 min
ACTH	Right CS	61 pg/mL [13.4 pmol/L]	172 pg/mL [37.9 pmol/L]	236 pg/mL [52.0 pmol/L]	449 pg/mL [98.9 pmol/L]	139 pg/mL [30.6 pmol/L]
	Left CS	46 pg/mL [10.1 pmol/L]	42 pg/mL [9.2 pmol/L]	39 pg/mL [8.6 pmol/L]	40 pg/mL [8.8 pmol/L]	42 pg/mL [9.2 pmol/L]
	PV	48 pg/mL [10.6 pmol/L]	37 pg/mL [8.1 pmol/L]	33 pg/mL [7.3 pmol/L]	39 pg/mL [8.6 pmol/L]	41 pg/mL [9.0 pmol/L]
	Right C/P ratio	1.27	4.65	7.15	11.5	3.39
	Left C/P ratio	0.96	1.14	1.18	1.03	1.02

Reference range: ACTH 7-63 pg/mL [SI: 1.5-13.9 pmol/L], cortisol 4.0-18.3 μg/dL [SI: 110.3-504.8 nmol/L].

Abbreviations: ACTH, adrenocorticotropic hormone; C/P ratio, central-to-peripheral ratio; CRH, corticotropin-releasing hormone; CS, cavernous sinus; DST, dexamethasone suppression test; PV, peripheral vein.

Figure 2.

Focal radionuclide uptake of the anterior mediastinum tumor in radiological examinations (yellow arrow). A, ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography. B, ¹¹¹In-pentetreotide somatostatin receptor scintigraphy.

Treatment

Robot-assisted thoracoscopic partial thymectomy was performed. Histopathological examination revealed the absence of necrotic zones and mitosis. Immunohistochemical staining of the tumor samples revealed positivity for chromogranin A, synaptophysin, CD56, somatostatin receptors 2 and 5, and ACTH (Fig. 3). The Ki-67 index was 1%. Therefore, the patient was diagnosed with ectopic CS due to an ACTH-secreting thymic typical carcinoid.

Figure 3.

Immunohistochemical findings of the thymic typical carcinoid tumor revealed positivity for chromogranin A, synaptophysin, CD56, somatostatin receptors 2 and 5, and ACTH (low and high magnifications). The Ki-67 proliferative index was 1%. Abbreviations: ACTH, adrenocorticotropic hormone; SSTR, somatostatin receptor.

Outcome and Follow-Up

After partial thymectomy, metyrapone was discontinued. Hydrocortisone replacement was continued. However, his plasma ACTH and serum cortisol levels did not increase (23 pg/mL [SI: 5.1 pmol/L] and 10.6 μg/dL [SI: 292.4 nmol/L], respectively) immediately after partial thymectomy. Therefore, hydrocortisone was gradually tapered and discontinued. His cushingoid features, including moon face, buffalo hump, central obesity, abdominal striae, and bruising, improved. A low-dose overnight DST 10 months after surgery significantly suppressed the serum cortisol level (0.9 μg/dL [SI: 24.8 nmol/L]).

Discussion

Herein, we present the relapse of ACTH-dependent cyclic CS after 19 years of remission. Additionally, the relapse immediately followed COVID-19 infection and treatment. To the best of our knowledge, this is the first case of relapsed ACTH-dependent cyclic CS involving COVID-19.

The increase of interleukin-6 during infection could stimulate cortisol secretion [6]. A meta-analysis demonstrated that serum cortisol levels were greater in COVID-19 patients than in healthy controls [7]. Therefore, the serum cortisol levels of the patient during COVID-19 infection may have been relatively high. Additionally, high-dose prednisolone for COVID-19 treatment was administered to the patient. A previous report showed that exogeneous glucocorticoids paradoxically increased the plasma ACTH and serum cortisol levels, leading to a relapse of the hypercortisolemic phase in cyclic CS [3]. This finding suggests that ACTH secretion in cyclic CS depends not on the glucocorticoid-driven system of negative feedback but on that of positive feedback. A recent study demonstrated that 8.7% of patients with CS may have a glucocorticoid-driven positive feedback status [4]. Therefore, the relapse of cyclic CS in the patient might be attributed to positive feedback from increased endogenous cortisol secretion due to COVID-19 infection and the use of exogenous glucocorticoids for COVID-19 treatment. The previous study demonstrated that hydrocortisone regulated POMC gene expression of thymic carcinoid via methylation of its promoter region [8].

On the other hand, trilostane and mitotane, which are steroidogenesis inhibitors, decreased the levels of plasma ACTH of the patient as well as those of serum cortisol and achieved tentative remission in the first hypercortisolemic phase of CS. Additionally, the steroidogenesis inhibitor metyrapone also induced remission in the second hypercortisolemic phase 19 years after the onset of CS. Steroidogenesis inhibitors reduce both plasma ACTH levels and serum cortisol levels in some reported cases, resulting in the remission of cyclic CS [3-5]. However, the mechanism remains unelucidated. The decrease in cortisol production caused by a steroidogenesis inhibitor might have inhibited ACTH secretion through the suppression of a positive feedback mechanism in this patient. However, the decrease of ACTH might be attributed to not the indirect effect of cortisol decrease but the direct effect of steroidogenesis inhibitors. Further research of the mechanism is required.

Moreover, hypercortisolemia correction may be accompanied by thymic hyperplasia, which confuses the localization of ectopic CS tumor, although the anterior mediastinum tumor of the present case was diagnosed as a thymic carcinoid [9]. ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography and somatostatin receptor scintigraphy demonstrated focal radionuclide uptake in the tumor. Therefore, these modalities could be useful for the differentiation between thymic carcinoid and hyperplasia.

In addition, the unique characteristic of the patient was 19 years of a significantly long trough phase of cyclic CS. The cycles of hypercortisolism in cyclic CS can range from a few days to many years [1, 10, 11]. Among reported cases with detailed examinations, the longest interval between hypercortisolemic phases was approximately 5 years [1, 10]. No symptoms and no abnormalities in annual medical checkups suggest a continued trough phase. Therefore, our patient has the longest trough phase (19 years) in reported cyclic CS cases. The patient might have remained in remission after 19 years due to lack of glucocorticoid positive feedback because the present case had never undergone any severe infections with cortisol increase and glucocorticoid treatments in the first trough phase.

On the other hand, there is discordance between the results of diagnostic tests and the final diagnosis by pathological examination. The ACTH-secreting thymic typical carcinoid of our patient might have high responsiveness to desmopressin, CRH, and high-dose dexamethasone because the accuracy of these tests is high but not perfect. Ectopic ACTH-secreting tumors occasionally respond to desmopressin, CRH, and high-dose dexamethasone suppression tests, due to the potential expression of vasopressin 2 receptor, CRH receptor, and glucocorticoid receptor [12, 13]. However, the plasma ACTH and serum cortisol levels remained within the reference ranges despite metyrapone cessation during the diagnostic tests and cavernous sinus sampling. The response of cortisol to a high-dose DST might be affected by cyclic cortisol activity [11]. Additionally, the diagnostic accuracy of inferior petrosal sinus or cavernous sinus sampling decreases during the trough phase [1]. Therefore, it was difficult to interpret the tests in the present case. During the trough phase, normalization of glucocorticoid negative feedback can recover ACTH secretion from normal corticotroph cells. Accordingly, diagnostic tests and cavernous sinus sampling in the trough phase could reflect ACTH secretion from normal corticotroph cells but not from ACTH-secreting tumors of CD or ectopic CS. As a result, a certain number of patients with ACTH-dependent cyclic CS have a risk of misdiagnosis. Diagnostic tests for cyclic CS should be performed during the hypercortisolemic phase.

A limitation of this case report is that the changes in the plasma ACTH and serum cortisol levels were not recorded from ages 37 to 49. However, no abnormalities were noted in annual medical checkups until the age of 44. Moreover, there were no cushingoid symptoms, such as weight gain, increased appetite, or moon face during the lost follow-up period. These findings suggest that there was no relapse of CS during this period.

In conclusion, we report a rare case of ACTH-dependent cyclic CS with relapse after a 19-year remission. Patients with uncured cyclic CS should require careful follow-up for relapse even if long-term remission of cyclic CS is achieved. Furthermore, physicians should pay attention to the development of cushingoid symptoms after infection stress and glucocorticoid treatment because a relapse of cyclic CS could be triggered by COVID-19 infection and glucocorticoid treatment, as in our patient.

Learning Points

• Long-term follow-up is essential in cases of uncured cyclic Cushing syndrome because of the risk of relapse even if long-term remission of cyclic CS is achieved.

• In cases of cyclic Cushing syndrome with a glucocorticoid-driven positive feedback mechanism, an exacerbation or a relapse of cyclic Cushing syndrome can be induced by stressful situations such as infection or the administration of glucocorticoids.

• Diagnostic tests for Cushing syndrome should be carefully interpreted during the trough phase of cyclic CS.

Abbreviations

ACTH

adrenocorticotropic hormone

CRH

corticotropin-releasing hormone

CS

Cushing syndrome

CD

Cushing disease

DST

dexamethasone suppression test

ref

reference range

Contributors

All authors made individual contributions to authorship. K.T., K.M., N.O., and S.M. were involved in the diagnosis and management of this patient. K.M. conceptualized the pathogenesis of this patient. K.T. and Y.O. acquired and analyzed the data of this patient. K.T., K.M., and Y.O. prepared the original draft. I.S. interpreted the data of this patient and revised the draft. All the authors reviewed and approved the final draft.

Funding

This case report was supported by Health Labour Sciences Research Grant (Japan Ministry of Health, Labour and Welfare: Number 23FC1042).

Disclosures

None declared.

Informed Patient Consent for Publication

Informed consent was obtained directly from the patient.

Data Availability Statement

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.