Types Of Cushing's Syndrome Research Articles

7385 Prevalence of Central Hypothyroidism in Cushing Syndrome and Thyroid Function Tests After Cushing Treatment

Abstract Disclosure: T. Kunavisarut: None. A. Sriwijitkamol: None. Cushing syndrome can be associated with thyroid dysfunction. We investigated the association between Cushing syndrome and thyroid dysfunction. We conducted a retrospective study at Siriraj Hospital in Thailand and analyzed thyroid function tests in 80 Cushing's patients. The inclusion criteria were patients diagnosed with Cushing syndrome with thyroid function tests recorded at diagnosis of Cushing syndrome. Patients who had an abnormal thyroid function test at diagnosis of Cushing syndrome must have a thyroid function test after treatment of Cushing syndrome. Of the 80 patients, sixty-five patients (81.2%) had normal thyroid function at diagnosis, 12 patients (15%) had central hypothyroidism and three patients (3.8%) had subclinical hyperthyroidism.Interestingly, among 12 patients who had central hypothyroidism, eight patients (66.7%) were diagnosed with Cushing disease. Three patients (25%) were diagnosed with adrenal Cushing syndrome and one patient (8.3%) was diagnosed with ectopic Cushing syndrome. This finding suggested that central hypothyroidism may not be exclusively due to the mass effect of the pituitary tumor on the normal pituitary because adrenal Cushing syndrome and ectopic Cushing syndrome can also cause central hypothyroidism. Among 12 patients with central hypothyroidism at diagnosis of Cushing syndrome, nine patients (75%) normalized their thyroid function after remission of Cushing syndrome without Levothyroxine replacement. Moreover, patients with central hypothyroidism had significantly higher median 24-hour urine-free cortisol levels than euthyroid patients (1030.5 ug/day vs. 404.5 ug/day, p=0.017), indicating a potential correlation between cortisol excess and low FT4 levels. These findings suggest that hypercortisolism in Cushing syndrome can suppress the hypothalamic-pituitary-thyroid axis, but this suppression is often reversible with successful Cushing's treatment. This study highlights the importance of central hypothyroidism, which can occur in all types of Cushing syndrome. If the patients did not have hypothyroid symptoms, Levothyroxine replacement may not be necessary. For patients who already received Levothyroxine and had normal thyroid function tests, Levothyroxine can be carefully tapered and potentially discontinued because successful Cushing syndrome treatment can ultimately normalize thyroid function tests. Presentation: 6/1/2024

Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) patient with ARMC5 mutations

BackgroundPrimary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a highly heterogeneous disease with divergent manifestations ranging from asymptomatic subclinical Cushing syndrome (CS) to overt Cushing syndrome with severe complications. ARMC5 mutations occur in 20 to 55% PBMAH patients usually with more severe phenotypes. Different ARMC5 mutations might be associated with diverse phenotypes of PBMAH.Case presentationA 39-year-old man was admitted to our hospital with progressive weight gain and severe hypertension. He presented typical CS and its classical metabolic and bone complications like hypertension and osteoporosis. The laboratory results showed high levels of cortisol and low levels of ACTH. Low- and high-dosed dexamethasone suppression tests were negative. Contrast-enhanced computed tomography (CT) revealed multiple bilateral irregular macronodular adrenal masses. Adrenal venous sampling (AVS) confirmed that the right adrenal gland with larger nodules secreted more hormone that the left side did. Right adrenalectomy and subsequent contralateral subtotal resection were conducted. His blood pressure and CS symptoms as well as comorbidities including backache and muscle weakness improved. Whole exome sequencing identified one ARMC5 germline mutation (c.1855C > T, p. R619*), five ARMC5 somatic mutations (four novel mutations) in his right and left adrenal nodules.ConclusionsThis PBMAH patient was identified with one ARMC5 germline mutation and five different somatic ARMC5 mutations (four novel mutations) in the different nodules of the bilateral adrenal masses. AVS combined with CT imagine could be helpful to determine the dominant side for adrenalectomy. Genetic testing is important for the diagnosis and management of the patient with PBMAH.

Clinical, Laboratory, and Treatment Profiles of Silent Corticotroph Adenomas That Have Transformed to the Functional Type: A Case Series With a Literature Review.

Purpose: Silent corticotroph adenoma (SCA) is clinically non-functional pituitary adenoma with expression of corticotropin or Tpit. To further understand the characteristics of this rare type of SCA transforming to a functional SCA, we retrospectively reviewed SCAs that converted to typical Cushing's syndrome at a tertiary medical center and the relevant literature.Methods: Patients were identified based on the diagnosis of pituitary adenoma without symptoms of hypercortisolism at the initial visit with positive Immunohistochemical (IHC) staining for corticotropin or Tpit after surgery and subsequent transformation to functional SCAs during the follow-up period from March 1990 to January 2020 at Peking Union Medical College Hospital and in the literature. The characteristics of the clinical manifestations, biochemical results, imaging findings, pathology findings and outcome were analyzed.Results: Altogether, 16 patients were included in the study with an average age of 42.0 ± 12.48 (18–65) years at the first visit. Females were slightly predominant (F:M = 1.3:1). The median time of conversion from the nonfunctional to the functional type was 30 (13.0, 68.3) months. Once a functional SCA developed, the adrenocorticotropic hormone (ACTH) level and 24-h urine free cortisol were increased 3.8- (2.6, 12.9) and 5.3- (2.6, 19.3) fold, respectively, above the normal range. Approximately 50% of the patients had macrocystic changes on pituitary MRI. All 16 patients experienced 1–5 surgeries with a median of 2.5 (2.0, 4.0) surgeries. The proportion of patients with Ki-67 ≥ 3% increased from 22.2% (2/9) at the beginning to 50% (7/14) at the time of functional SCA diagnosis. Thirteen patients received radiotherapy, and 4 patients (30.8%) achieved remission. Four patients with refractory functional SCAs received temozolomide treatment with the normalization of cortisol in 4 cases and reduced tumor volume in 3 cases.Conclusion: In this study, all cases that transformed to functional SCAs were macroadenomas. Hypercortisolism was more severe in functional SCA patients. The tumors tended to have frequent recurrence and were highly invasive. Temozolomide could be a promising treatment for refractory functional SCA cases. Long-term follow-up is needed for nonfunctional SCAs since some cases have the potential to transform to clinical Cushing's syndrome.

Iatrogenic Cushing Syndrome in Patients Receiving Inhaled Budesonide and Itraconazole or Ritonavir: Two Cases and Literature Review

ObjectiveTo present two cases of iatrogenic Cushing syndrome caused by the interaction of budesonide, an inhaled glucocorticoid, with ritonavir and itraconazole. MethodsWe present the clinical and biochemical data of two patients in whom diagnosis of Cushing syndrome was caused by this interaction. We also reviewed the pertinent literature and management options. ResultsA 71-year-old man was treated with inhaled budesonide for a chronic obstructive pulmonary disease and itraconazole for a pulmonary aspergillosis. The patient rapidly developed a typical Cushing syndrome complicated by bilateral avascular necrosis of the femoral heads. Serum 8:00 AM cortisol concentrations were suppressed at 0.76 and 0.83 µg/dL on two occasions. The patient died 4 days later of a massive myocardial infarction. The second case is a 46-year-old woman who was treated for several years with inhaled budesonide for asthma. She was put on ritonavir, a retroviral protease inhibitor, for the treatment of human immunodeficiency virus (HIV). In the following months, she developed typical signs of Cushing syndrome. Her morning serum cortisol concentration was 1.92 µg/dL. A cosyntropin stimulation test showed values of serum cortisol of <1.10, 2.65, and 5.36 µg/dL at 0, 30, and 60 minutes, respectively, confirming an adrenal insufficiency. Because the patient was unable to stop budesonide, she was advised to reduce the frequency of its administration and eventually taper the dose until cessation. ConclusionClinicians should be aware of the potential occurrence of iatrogenic Cushing syndrome and secondary adrenal insufficiency due to the association of inhaled corticosteroids with itraconazole or ritonavir. (Endocr. Pract. 2013;19:e138-e141)

Clinical features of 131 patients with Cushing syndrome

One hundred and thirty-one patients with Cushing syndrome (33 males and 98 females) were enrolled,including 53 cases of Cushing's disease,49 cases of adrenal adenoma,12 cases of big nodular hyperplasia,16 cases with ectopic ACTH syndrome,and 1 case with adrenal cortical carcinoma.The age of onset,duration,8:00 and 0:00 plasma cortisol levels,24 h urinary free cortisol levels,fasting plasma glucose,HbA1C,8:00 cortisol level after high-and low-dose dexamethasone suppression test were significantly different among different types of Cushing syndrome (all P＜0.05).The primary lesion in 16 cases of ectopic ACTH syndrome were found in lung (n =5),pancreas (n =3),thymus (n =2),liver (n =2),and unknown origin (n =4).There were 60 cases combined with diabetes(45.8％),22 cases with impaired glucose tolerance (16.8％),and 49 cases with normaglycemia (37.4％) in these 131 patients.The probability of Cushing syndrome in female was higher than that in man.There were significantly different for the clinical manifestations and biochemical parameters among different types of Cushing syndrome.Abnormal glucose metabolism is the common clinical manifestations of patients with Cushing syndrome. Key words: Cushing syndrome; Clinical features

Usefulness of composite methionine–positron emission tomography/3.0-tesla magnetic resonance imaging to detect the localization and extent of early-stage Cushing adenoma

Fifty to eighty percent of Cushing disease is diagnosed by typical endocrine responses. Recently, the number of diagnoses of Cushing disease without typical Cushing syndrome has been increasing; therefore, improving ways to determine the localization of the adenoma and making an early diagnosis is important. This study was undertaken to determine the present diagnostic accuracy for Cushing microadenoma and to compare the differences in diagnostic accuracy between MR imaging and PET/MR imaging. During the past 3 years the authors analyzed the diagnostic accuracy in a series of 35 patients with Cushing adenoma that was verified by surgical pituitary exploration. All 35 cases of Cushing disease, including 20 cases of "overt" and 15 cases of "preclinical" Cushing disease, were studied. Superconductive MR images (1.5 or 3.0 T) and composite images from FDG-PET or methionine (MET)-PET and 3.0-T MR imaging were compared with the localization of adenomas verified by surgery. The diagnostic accuracy of superconductive MR imaging for detecting the localization of Cushing microadenoma was only 40%. The causes of unsatisfactory results for superconductive MR imaging were false-negative results (10 cases), false-positive results (6 cases), and instances of double pituitary adenomas (3 cases). In contrast, the accuracy of microadenoma localization using MET-PET/3.0-T MR imaging was 100% and that of FDG-PET/3.0-T MR imaging was 73%. Moreover, the adenoma location was better delineated on MET-PET/MR images than on FDG-PET/MR images. There was no significant difference in maximum standard uptake value of adenomas evaluated by MET-PET between preclinical Cushing disease and overt Cushing disease. Composite MET-PET/3.0-T MR imaging is useful for the improvement of the delineation of Cushing microadenoma and offers high-quality detectability for early-stage Cushing adenoma.

Exaggerated Response of Adrenocorticotropic Hormone to Growth Hormone-Releasing Peptide-2 Test in Cushing's Disease -Case Report-

A 47-year-old woman presented with a pituitary microadenoma manifesting as typical Cushing's syndrome. The diagnosis was Cushing's disease based on the endocrinological findings. Plasma adrenocorticotropic hormone (ACTH) levels were greatly increased from 66 pg/ml to 2490 pg/ml (about 38-fold) in response to the administration of 100 microg human growth hormone-releasing peptide (GHRP)-2. GHRP receptor type 1a messenger ribonucleic acid was detected in the tumor. Therefore, GHRP-2 may stimulate ACTH via the GHRP receptor type 1a in pituitary ACTH-producing tumor. The GHRP-2 test, currently clinically available in Japan, may be a useful diagnostic tool for Cushing's disease.

Management of ACTH-secreting supradiaphragmatic adenomas

Supradiaphragmatic adrenocorticotropic hormone (ACTH) secreting pituitary adenomas are exceptionally encountered (14 cases previously described) and raise issues concerning their nosology and management. If surgery is the treatment of choice, the nature of surgical approach (craniotomy, transsphenoidal approach) remains controversial. To illustrate this issue, we presented two cases of supradiaphragmatic ACTH secreting pituitary adenomas successfully excised via a subfrontal approach. Both patients were female (20 and 41 years) and had a typical Cushing's syndrome. MRI revealed, in both cases, a suprasellar mass in contact with the pars tuberalis of the pituitary. In the first case, the patient underwent initially a transsphenoidal approach with negative exploration and subsequent partial hypophysectomy. One year later, the patient was operated on again via a subfrontal approach, allowing excision of a supradiaphragmatic adenoma and a complete cure of Cushing's disease. In the second case, the patient underwent initially a subfrontal approach and was definitely cured. In both cases, the diaphragma sellae was found to be intact and the pituitary stalk could be preserved. Postoperative MRI demonstrated a clearly visible intact pituitary stalk in conjunction with normal aspect of the pituitary. Supradiaphragmatic pituitary adenomas are most likely adenomas of the pituitary stalk with extra-axial development. Surgery remains the treatment of choice. Should the superior approach be preferred, the transsphenoidal-transtuberculum sellae approach may represent a viable alternative when performed by a well-trained surgical team. Surgery may be difficult, and drawbacks are non negligible, particularly in elderly patients. In these cases, stereotactic radiosurgery should receive more consideration.

Adrenocorticotropic hormone (ACTH) increases the expression of its own receptor gene.

Regulation of the ACTH receptor (R) in the adrenal gland by its own ligand "ACTH" has been a matter of controversy. In the present study, whether ACTH regulates the expression of mRNA for its own receptor in the adrenal gland was studied in human subjects and in rats in vivo. In the human study, adrenal adenoma tissues as well as adjacent normal tissues were obtained at surgery from two patients with typical Cushing's syndrome. Northern blot analysis revealed two ACTH-R mRNA species with 4.0 kb and 2.0 kb. ACTH-R mRNAs in the adenoma tissues were much more abundant than those in the normal tissues from the two patients, suggesting that the mRNA in normal adrenal tissue is either suppressed by cortisol excess or the absence of ACTH. To examine the mechanism involved in ACTH-R mRNA regulation, the changes in the receptor mRNA caused by ACTH were studied in dexamethasone-treated rats. Administration of dexamethasone for 5 days resulted in a marked decrease in ACTH-R mRNA to an undetectable level. A bolus administration of ACTH1-24 intravenously or ACTH-Z1-24 intramuscularly to the dexamethasone-treated rat did not cause any significant change in ACTH-R mRNA from 0.5 to 12 h after the administration. However, a significant increase in the receptor mRNA was observed at 24 h after the ACTH-Z1-24 and the level was further increased until 48 h followed by a sustained increase at 72 h when it was given once every 24 h. These data suggest that the ACTH-receptor is increased by ACTH at a pretranslational level.(ABSTRACT TRUNCATED AT 250 WORDS)

Argyrophil cell carcinoma of the uterine cervix with ectopic production of acth, β-MSH, serotonin, histamine, and amylase

The case of a 38-year-old female with primary argyrophil cell carcinoma of the uterine cervix is reported. Two years after operation the patient developed widespread metastases with typical Cushing's syndrome. Microscopically, the tumor consisted of solid anaplastic cells, adenocarcinoma, and squamous cells. The plasma levels of ACTH and cortisol were elevated. Many cells of both the primary and metastatic tumors showed argyrophilia. Almost all the cells of the metastases contained numerous round secretory granules measuring about 117 micrometers in diameter. Small rod-shaped or larger round secretory granules, measuring 250 and 430 micrometers respectively, were also found in a few of these cells. The tumors in the right lung, pancreas, and kidney contained high levels of ACTH, beta-MSH, serotonin, histamine, and amylase. This is the first report of ectopic production of these five substances from argyrophil cell carcinoma of the uterine cervix.

Concurrent hypersecretion of aldosterone and cortisol from the adrenal cortical adenoma

Hypertension, hypokalemia, suppressed plasma renin activity and increased plasma aldosterone were found in a middle-aged woman. Following removal of the tumor in the left adrenal gland these abnormalities disappeared. Concurrently, however, the plasma cortisol level did not show normal diurnal change, although the value at 6 A.M. was within the normal range. Administration of 2 mg dexamethasone failed to depress the plasma cortisol level and urinary 17-OHCS concentration. Postoperatively, plasma cortisol and urinary 17-OHCS were below normal. Histologic examination of the tumor indicated the presence of two types of adenoma cells; one was a large watery clear cell with rich lipid and possibly with aldosterone secretion and the other was an acidophilic cell with poor lipid and possibly with cortisol secretion. It is suggested that, in addition to oversecretion of aldosterone, the tumor autonomously secreted cortisol, although the amount of cortisol secreted was not large enough to produce typical Cushing's syndrome.

Gastric carcinoid with ectopic production of ACTH and β-MSH

A 51-year-old woman with typical Cushing's syndrome of about 9 years duration was shown to have a gastric carcinoid tumor. Plasma levels of ACTH and cortisol were elevated and lacked the normal diurnal rhythm. Urinary excretion of steroids was unaffected by the administration of either metyrapone or dexamethasone. Fluctuation in urinary steroid excretion, as well as transient hypokalemic alkalosis and glycosuria suggested periodic hormonogenesis. The extirpated gastric carcinoid was shown to contain immunoreactive ACTH and beta-MSH. However, the biologic ACTH activity was undetectable by in vivo steroidogenic assay. By gel filtration, it was demonstrated that both tumor and plasma ACTH was predominately "big" ACTH. Although postoperatively she developed hypoadrenocorticism severe enough to require ACTH treatment, her pituitary-adrenal function was gradually restored. This is the first documented case of ectopic ACTH syndrome caused by gastric carcinoid in which successful cure was achieved by surgery.

A CASE OF DWARFISM ACCOMPANIED BY CUSHING'S SYNDROME AND SOME FEATURES OF VIRILIZATION

An 18-year-old girl, who presented manifestations of dwarfism and typical Cushing's syndrome as well as some features of virilization, was presented. Height-and weight-age of the patient were 10 and 121/2 years, respectively. In spite of an increased androgen as was indicated by presence of an enlarged clitoris and increased output of 17-KS, retardation of osseous development and epiphyseal fusion was disclosed in x-rays of bones. These findings are attrib-utable to excessive secretion of glucocorticoids overwhelming the effect of androgen. At the same time, however, the increase in serum alkaline phos-phatase level suggests the presence of an accelerated osteoblastic activity.The removal of the left adrenal, which was almost normal in appearance resulted in marked improvement of clinical and. laboratory findings such as lowered blood pressure, restoration of regular menstruation, disappearance of glucosuria, normal circulating eosinophil, disappearance of hypernatremia and return of urinary corticosteroids to normal.

Personality changes in Cushing's syndrome.

IN THE past five years there has been an increasing number of reports describing mental disturbances precipitated by treatment with ACTH and cortisone (1, 2). Another sequel of administering excess ACTH is the occurrence of the typical Cushing's syndrome (3). Thus there arises the question whether the hormonal changes that are responsible for this syndrome may not also represent a chemical basis for the psychiatric changes. Since the original description by Dr. Cushing in 1932 (4), various authors have recognized that mental disturbances are frequent concomitants of the syndrome. Many papers make brief or casual reference to extreme depression and dullness. In the past, however, these emotional alterations have almost always been attributed to poor social adjustment secondary to the often repulsive appearance of these patients. The mental symptoms were regarded as nonspecific affective disorders which were interpreted as the result of self-consciousness. Maclay and Stokes (5) and Schlesinger and Horwitz (6) were among the first to suggest specificity in the relation between the psychosis and endocrine dysfunction in this syndrome.

A PITUITARY SYNDROME

Cushing1described a syndrome known as the basophilic syndrome of the pituitary gland, the clincal characteristics of which are: (1) adiposity of the face and trunk, usually sparing the extremities; (2) amenorrhea, or sexual impotence in the male; (3) hypertrichosis of the face and trunk (masculine in type) in females and in adolescent males, and possibly the reverse in adult males; (4) dusky or plethoric skin, with purplish lineae atrophicae, acrocyanosis, cutis marmorata and purpura-like ecchymoses; (5) vascular hypertension; (6) a tendency to polycythemia and polynucleosis; (7) osteoporosis, with softening of the bones of the skeleton and kyphosis; (8) headache, pain in the back, asthenia and fatigability; (9) hyperglycemia and albuminuria, and (10) intracranial signs, with exophthalmos, diplopia, papilledema, dimness of vision, polyphagia, polydipsia and polyuria. Pardee2reported seven cases of pituitary basophilism, two of which presented the typical Cushing syndrome and five, so-called atypical or variable syndromes.