Correspondence to: Koji Shibuya, Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan. Tel: +81-285-58-7355 Fax: +81-285-44-8143 E-mail: [email protected]
Case Report
A case of cyclic Cushing s disease requiring short-term hormone replacement therapy after surgery
Cyclic Cushing s syndrome (CS) is a rare disease defined as a periodic excessive production of cortisol.
Here, we report a case of a 55-year-old woman diagnosed with Cushing s disease (CD) with intermittent increases in cortisol levels, indicating cyclic CD. Contrast-enhanced magnetic resonance imaging and surgery revealed a pituitary adenoma beside a cystic lesion. After surgical treatment, although the patient temporarily presented with adrenal insufficiency, she could discontinue hormone replacement therapy only 4 months later. This report suggests that a patient with cyclic CD can cease postoperative hormone replacement therapy within a short period.
(Key words: adrenal insufficiency, cyclic Cushing s disease, hormone replacement therapy) Abstract
1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
2. Department of Neurosurgery, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
Koji Shibuya1, Manabu Takahashi1, Takeshi Nakajima2, Tomoyuki Kurashina1, Shuichi Nagashima1, Kenta Okada1, Ken Ebihara1, Kensuke Kawai2, Shun Ishibashi1
Introduction
Cyclic Cushing s syndrome (CS) is a rare disease characterized by cyclic or intermittent changes in cortisol levels. Cyclic CS is often difficult to diagnose because of a large fluctuation in serum cortisol levels. Delayed diagnosis could lead to complications that significantly impair the patient s quality of life. To date, multiple cases of cyclic CS have been reported; however, there are no clear descriptions and guidelines for its pathophysiology or treatment. We herein report a case of cyclic Cushing s disease (CD) due to a pituitar y microadenoma that was juxtaposed with (or was adjacent to) a cystic lesion and required short- term postoperative hormone replacement therapy. This case suggests that patients with cyclic CS may be able to discontinue hormone replacement therapy earlier than usual after surgery. Long-term corticosteroid replacement therapy can impair the patient s quality of life; therefore, it should be reduced as early as possible. Our case may provide a perspective on the duration of postoperative hormone replacement therapy in cyclic CD.
Case
A 55-year-old woman who had been treated for diabetes, hypertension, and dyslipidemia for over 10 years was referred to our hospital for diabetes control. During outpatient examination, she complained of insomnia, mood swings, increased appetite, and weight gain. She was overweight (body mass index, 27.1 kg/m2) and presented with Cushing s signs, such as moon face, buffalo hump, central obesity, and hirsutism. Her blood pressure was 161/102 mmHg. Results of laboratory blood tests showed leukocytosis with neutrophilia, mild thyroid dysfunction (FT3, 1.75 pg/mL), high HbA1c (12.3%), normal serum cortisol levels (15.0μg/dL), high adrenocorticotropic hor mone (ACTH) levels (93.4 pg/mL), and high dehydroepiandrosterone sulfate levels (220μg/dL) (Table 1). Bone density was the lower limit of normal (82%
in young adult mean).
She was hospitalized because her blood test results strongly suggested a diagnosis of CD. Moreover, her past medical history of pneumatosis cystoides intestinalis at the age of 45 indicated excess production of cortisol. Because the circadian rhythm of serum cortisol was maintained on
the first day of hospitalization, we measured her serum cortisol levels at various times over multiple days. In 2 weeks, she had intermittent large increases in serum cortisol and ACTH levels (Fig. 1A). The 24-h urinary free cortisol (UFC) levels were normal in the first measurement (43.0 μg/day) but high in the second measurement (183 μg/day). An overnight dexamethasone suppression test showed that the serum cortisol levels were significantly suppressed by a high dose of dexamethasone (8 mg) but not by a low dose (0.5 mg) (Table 2A). A large increase in ACTH levels was observed by the corticotropin-releasing hormone (CRH) test (Table 2B). Considering the hormone measurement in the outpatient examination (Fig. 1B), these findings confirmed the diagnosis of cyclic CD with intermittent fluctuations of serum levels of cortisol and ACTH. Contrast-enhanced magnetic resonance imaging (MRI) of the pituitary gland showed a cystic lesion on the left side of the anterior lobe, but there was no obvious pituitar y adenoma (Fig. 2A). A computed tomography scan of the adrenal gland revealed low-density nodules in both adrenal glands, which were consistent with adrenal hyperplasia (Fig. 2B). Although the pituitary adenoma could not be confirmed on MRI, both the clinical pictures and the laboratory data strongly supported the diagnosis
of a pituitary microadenoma. To make a precise diagnosis, bilateral simultaneous cavernous sinus sampling was performed. Moreover, the central/peripheral ratio (C/P ratio) of ACTH was high, suggesting ACTH-dependent CD (Table 2C).
Although cortisol levels fluctuated intermittently, a small dose of metyrapone (250–500 mg/day) was administered prior to surgery due to the fact that most of the follow-up period suggested active phase and the patient s symptoms were severe. Then, the patient underwent transsphenoidal surgery under adequate diabetic control using insulin and infection control using antibiotics. A pale-yellow fibrous tissue that was different from the normal pituitary gland was found near the lesion of the cyst containing serous fluid. Both lesions were resected subsequently (Fig. 2C).
On immunohistochemical examinations, the adenoma cells were positive for ACTH, T-pit and somatostatin receptor type 5 (SSTR5), which were compatible with CD. Cytokeratin (CAM5.2) staining showed a densely granulated adenoma (Fig. 3).
After the operation, because the patient presented with transient diabetes insipidus and hypocortisolemia, hormone replacement therapy (20 mg/day of hydrocortisone and 60 μg/day of desmopressin orally disintegrating tablet) Table 1. Clinical and biochemical data.
Before surgery After surgery Normal range
SBP/DBP (mmHg) 161/102 100/72 130/80
BMI (kg/m2) 27.1 24.85 18.5-25
WBC (/μL) 10490 5200 3300-8600
Neu (%) 83.4 53.7 40.0-71.0
Lym (%) 12.1 32.4 25.0-50.0
Eos (%) 0.3 2.3 0.0-5.0
Na (mmol/L) 142.4 143 138-145
K (mmol/L) 3.7 3.8 3.6-4.8
TG (mg/dL) 147 163 30-117
HDL-C (mg/dL) 61.8 63 48-103
LDL-C (mg/dL) 132.8 140 <139
FPG (mg/dL) 167 98 73-109
HbA1c (%) 12.3 6.6 4.9-6.0
ACTH (pg/mL) 93.4 23.2 7.2-63.3
Cortisol (μg/dL) 15 5 6.24-18.0
TSH (μU/mL) 0.8 0.92 0.45-3.33
FT3 (pg/mL) 1.75 2.47 2.11-3.51
FT4 (ng/dL) 1.09 1 0.84-1.44
GH (ng/mL) 0.77 0.3 <2.1
IGF-1 (ng/mL) 237 136 74-208
PRL (ng/mL) 6.77 10.1 3.12-15.39
LH (mIU/mL) 18.28 10 14.4-62.2
FSH (mIU/mL) 43.71 32 36.6-168.8
DHEA-S (μg/dL) 220 113 8-188
UFC (μg/day) 183 35.5 11.2-80.3
Day0 Day1 Day7 Day14
Time 21:00 8:00 12:00 21:00 8:00 12:00 21:00 8:00 12:00 21:00
Cortisol (μg/dL) 2.2 11.6 17.1 12.1 9.3 14.4 21.2 20.5 12.7 19.8
ACTH (pg/mL) 13.5 43.2 159.0 54.2 28.3 38.3 77.5 74.5 19.5 59.5
UFC (μg/day)
Phase inactive active inactive active inactive active
A
43.0 183.0
Metyrapone Hydrocortisone 25
20 15 10 5 0
100 80 60 40 20
0 1 2 6 9 10 11 12 13 14 15 17 19 21 23 0
Bilateral simultaneous cavernous
sinus sampling Surgery Functional endocrine test
Cortisol (μg/dL) ACTH(pg/mL)
250mg 500mg
20mg 15mg
Cortisol ACTH
Time (month)
B
Figure 1. Serum cortisol and adrenocorticotropic hormone (ACTH) levels. (A) Hormone levels during hospitalization.
Serum hormone levels were evaluated three times per day (8:00, 12:00 and 21:00). (B) Clinical course and hormone levels during outpatient consultation. Cortisol and ACTH levels were measured from 8:00 to 12:00. ACTH cutoff value: 7.2–63.3 pg/
mL, cortisol cutoff value: 6.24–18.0 μg/dL (from 8:00 to 12:00), >5.0 μg/dL (21:00).
A
Dexamethasone suppression test
Before 0.5 mg 8 mg
Cortisol (μg/dL) 15.0 10.2 2.0
ACTH (pg/mL) 93.4 28.7 9.0
C
Bilateral simultaneous cavernous sinus sampling
ACTH (pg/mL) / Time after CRH stimulating -3 min 0 min 3 min 5 min 10 min
Right femoral vein 29.5 28.6 27.5 39.2 53.8
Right cavernous sinus 169.0 64.5 5336.0 1179.0 1590.0
Left cavernous sinus 1552.0 442.6 1958.0 838.6 739.8
B
Corticotropin-releasing hormone (CRH) test
Before 30 min 60 min 90 min
Cortisol (μg/dL) 19.6 26.7 24.9 18.4
ACTH (pg/mL) 77.7 180.0 118.0 55.9
Table 2. Results of endocrine function tests.
was performed. Four months later, functional endocrine tests such as rapid ACTH test and CRH test indicated normal adrenocortical and pituitary function; therefore, hydrocortisone and desmopressin were tapered off and finally discontinued during hospitalization. Cortisol and ACTH remained in normal levels even after the treatment was discontinued (Fig. 1B). The doses of therapeutic drugs were reduced since hyperglycemia, hypertension and dyslipidemia were improved (Table 1, 3), and most of the symptoms (insomnia, mood swings, increased appetite, and weight gain) disappeared. Over 2 years have passed after surgical treatment, and no recurrence of hypercortisolemia has been observed to date.
Discussion
CS is caused by pituitar y adenomas, ectopic ACTH- producing tumors, and adrenocor tical carcinoma or
hyperplasia. CS is rare, occurring in 0.7–2.4 people per million per year1. Among these people, those who exhibit cyclic or intermittent changes in cortisol levels are reported as having cyclic CS2. Although no clear clinical guidelines for the diagnosis and management of cyclic CS are available thus far, the diagnosis of cyclic CS has been made when the patients had cyclic increases of cortisol levels with at least three peaks and two troughs, or sometimes two peaks and one trough2-4. Cycle lengths of inappropriate cortisol production were extremely variable spanning from 12 h to 85 days5. Although the exact incidence (or prevalence) of cyclic CS is still unclear, it was reported to be 11%, 54%, and 26% for adrenocortical tumors, pituitary adenomas, and ectopic ACTH-producing tumors, respectively2. Although transsphenoidal surgery is the first choice for the treatment of cyclic CD, the disease has high rates of recurrence, with the cure and recurrence rates being 25%
Before surgery After surgery
for diabetes
canagliflozin 100 mg/day metformin 1500 mg/day mitiglinide 10 mg/day dulaglutide 0.75 mg/week
metformin 1250 mg/day vildagliptin 100 mg/day
for hypertension amlodipine 10 mg/day
telmisartan 40 mg/day –
for dyslipidemia bezafibrate 200 mg/day pravastatin 10 mg/day
Table 3. Changes of medication.
Figure 3. Histopathological staining. (A) Hematoxylin and eosin staining. (B) Silver impregnation staining. (C) Cytokeratin (CAM5.2) staining. (D) Staining for adrenocorticotropic hormone (ACTH). (E) Staining for T-pit. (F) Staining for somatostatin receptor 5 (SSTR5). ACTH positive, T-pit positive, and SSTR5 positive were compatible with CD. CAM5.2 staining showed a densely granulated adenoma. Crooke hyaline degeneration of normal pituitary cells was mild. Original magnifications are (A, B) ×40 and (C, D, E, F) ×200.
A B C
D E F A B C
Figure 2. Imaging studies and intraoperative findings. (A) Contrast-enhanced magnetic resonance imaging of the pituitary gland. The top and bottom figures are T1- and T2-weighted images, respectively. Red arrows indicate cystic lesion. (B) Computed tomography scan of the adrenal gland. Red arrows indicate possible adrenal hyperplasia in the adrenal nodules. (C) Intraoperative findings. The white arrow indicates cyst and pituitary adenoma.
and 63%, respectively6. Based on these reports, the case we encountered could be identified as cyclic CD because of the fluctuation in serum cortisol levels.
Noteworthily, this case had two features that were distinct from the previous cases in the literature. The first feature is the finding on the recovery of adrenocortical function after surgery. It is well known that patients with CS exhibit hypocortisolemia after surgery due to dysfunction of the hypothalamic-pituitary-adrenal axis. Berr et al. reported that the median recovery time of adrenocortical function in patients with regular CD was 1.4 years7. In our case, it took only approximately 0.3 years to recover the adrenocortical function and discontinue hormone replacement therapy. The term to recover adrenocortical function was much earlier than that in average patients with regular CD. W drychowicz et al. also reported that a 7-year-old patient with cyclic CD could discontinue hydrocortisone supplementation 4 months after surgery8. It has been reported that higher doses and longer use of exogenous corticosteroids give a high risk of adrenal insufficiency9. In this case, although the ability of the tumor to produce ACTH was simply mild, it was suggested that early withdrawal of postoperative hormone replacement therapy was possible because this case had periods of normal cortisol secretion long enough to alleviate atrophy of ACTH-producing cells in the normal pituitary gland. Replacement of corticosteroids should be withdrawn as soon as possible because the side effects are problematic.
Although our findings suggest that a patient with cyclic CD can discontinue postoperative hormone replacement therapy earlier than regular CD, further investigation in similar cases is necessary due to the fact that few cases with cyclic CD were reported. Careful observation must be needed because cyclic CD has high rates of recurrence6. However, in our case, there has been no evidence of recurrence to date.
The second feature is the fact that the pituitary adenoma- induced cyclic CD coexisted with a cystic lesion. In cyclic CD, although the factors that cause fluctuations in cortisol levels have not been clarified, multiple hypotheses have been proposed as the underlying mechanisms. Bleeding from the tumor, synchronized tumor cell growth and cell death, and partial necrosis of the tumor may cause periodic or intermittent production of cortisol2, 10. Another mechanism may be fluctuations in the adrenal–pituitary axis feedback; fluctuations in the secretion of neurotransmitters that contribute to ACTH secretion; or influence of dopamine, serotonin, or inflammatory cytokines2, 10. Cystic lesions can be a manifestation of cystic pituitary adenoma, craniophar yngioma, arachnoid cyst and Rathke s cleft cyst. Although Rathke s cleft cyst is the most common, we did not have pathological evidence for it. It is unclear whether the cystic lesion and pituitary adenomas coexisted coincidentally, or whether the cystic lesion was related to
the fluctuations in ACTH production of ACTHoma.
In conclusion, we report a case of cyclic CD requiring postoperative hormone replacement therapy for a short period of time. To the best of our knowledge, few reports of cyclic CD have described hormone replacement therapy after surgery. Further studies are warranted to understand the pathogenesis and treatment of cyclic CD.
Declaration of interest
The authors have no conflict of interest to declare.
Acknowledgements
We thank Dr. Naoko Inoshita at the Department of Pathology, Tokyo Metropolitan Geriatric Medical Center, for the pathological diagnosis. We would like to thank Editage (www.editage.com) for English language editing.
References
1. Newell-Price J, Ber tagna X, Grossman AB, et al.
Cushing s syndrome. Lancet 2006; 367: 1605-1617.
2. Meinardi JR, Wolffenbuttel BHR, Dullaart RPF. Cyclic Cushing s syndrome: a clinical challenge. Eur J Endocrinol 2007; 157: 245-254.
3. wi tkowska-Stodulska R, Berli ska A, Stefa ska K, et al. Cyclic Cushing s syndrome - A diagnostic challenge.
Front Endocrinol (Lausanne) 2021; 12: 658429.
4. Jahandideh D, Swearingen B, Nachtigall LB, et al.
Characterization of cyclic Cushing s disease using late night salivary cortisol testing. Clin Endocrinol (Oxf) 2018; 89: 336-345.
5. Shapiro MS, Shenkman L. Variable hormonogenesis in Cushing s syndrome. Q J Med 1991; 79: 351-363.
6. Asano S, Ooka H, Okazaki R, et al. Long-term remission of cyclic Cushing s disease that was diagnosed and treated surgically non-active phase. Endocr J 2007; 54:
407-412.
7. Berr CM, Dalmazi GD, Osswald A, et al. Time to recovery of adrenal function after curative surgery for Cushing s syndrome depends on etiology. J Clin Endocrinol Metab 2015; 100: 1300-1308.
8. W drychowicz A, Hull B, Kalicka-Kasperczyk A, et al.
Cyclic Cushing s Disease in the Prepubertal Period-A Case Report and Review of Literature. Front Endocrinol (Lausanne) 2019; 10: 701.
9. Broersen LHA, Pereira AM, Jørgensen JOL, et al.
Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. J Clin Endocrinol Metab 2015; 100: 2171-2180.
10. Albiger NME, Scaroni CM, Mantero F. Cyclic Cushing s syndrome: an overview. Arq Bras Endocrinol Metabol 2007; 51: 1253-1260.
要 約
連絡先：澁谷 浩史，自治医科大学内科学講座内分泌代謝学部門，〒329-0498 栃木県下野市薬師寺3311-1．
Tel：0285-58-7355, Fax：0285-44-8143 E-mail：[email protected]
周期性クッシング症候群はコルチゾールの周期的な過剰産生を呈する稀少な疾患である。我々は今回，間歇的なコルチ ゾール値の上昇を示し周期性クッシング病と診断した55歳の女性を経験したため報告する。造影MRI検査および術中所見 より，嚢胞性病変に隣接する下垂体腺腫の存在が明らかとなった。外科的治療後，本例は一時的に副腎皮質機能不全を呈 しホルモン補充療法を要したが，わずか４ヶ月後にはホルモン補充療法を中止することが可能であった。本症例は周期性 クッシング病患者が，外科的治療後のホルモン補充療法を短期間で中止できる可能性を示唆している。
（キーワード：副腎皮質機能不全，周期性クッシング病，ホルモン補充療法）
１．栃木県下野市薬師寺3311-1 自治医科大学内科学講座内分泌代謝学部門 ２．栃木県下野市薬師寺3311-1 自治医科大学脳神経外科学講座
澁谷 浩史１，高橋 学１，中嶋 剛２，倉科 智行１，永島 秀一１，岡田 健太１，海老原 健１， 川合 謙介２，石橋 俊１