Medical Therapy of Cushing's Disease

Surgical excision of an ACTH-producing pituitary tumor is the optimal therapy for Cushing's disease. However, medical therapy may have either a primary or adjunctive role if the patient cannot safely undergo surgery, if surgery fails, or if the tumor recurs. When medication is the only therapy, a major disadvantage is the need for lifelong therapy; in general, recurrence follows discontinuation of treatment. These compounds work through three broad mechanisms of action. Neuromodulatory compounds modulate corticotropin (ACTH) release from a pituitary tumor, steroidogenesis inhibitors reduce cortisol levels by adrenolytic activity and/or direct enzymatic inhibition and glucocorticoid antagonists block cortisol action at its receptor.In general, neuromodulatory compounds (bromocriptine, cyproheptidine, somatostatin and valproic acid) are not very effective agents for Cushing's disease. Treatment with a glucocorticoid antagonist and radiation therapy has been reported on a single patient only. Steroidogenesis inhibitors, including mitotane, metyrapone, ketoconazole, and aminoglutethimide, are the agents of choice for medical therapy of Cushing's disease. In general, ketoconazole is the best tolerated of these agents and is effective as monotherapy in about 70% of patients. Mitotane and metyrapone may be effective as single agents, while aminoglutethimide generally must be given in combination. The intravenously-administered etomidate may used when patients cannot take medications by mouth.     

Spine Abnormalities and Damage in Patients Cured from Cushing's Disease

The skeletal system is a common target of glucocorticoids. Structural and functional impairment of skeletal system is a relevant cause of morbidity and disability in patients with Cushing's syndrome.Thirty-six patients long-term (3.9 ± 0.5 yrs) cured from Cushing's disease (CD), 26 with adulthood-onset CD (AOCD) and 10 with childhood-onset CD (COCD) and 2 groups of controls, 24 age- and sex-matched patients with nonfunctioning pituitary adenomas (NFA) and 36 age- and sex-matched healthy subjects (HS), entered this open transversal controlled study to evaluate the prevalence of spine abnormalities and damage by standard radiography in subjects with a history of Cushing's syndrome.Symptoms and signs of backache were present in 86.1% CD patients (100% COCD and 80.8% AOCD), in 30.5% HS (² = 20.6, p < 0.0001) and 37.5% NFA patients (² = 13.2, p < 0.0001). The prevalence of trabecular bone rarefaction (² = 6.5, p < 0.01 and ² = 4.5, p < 0.05), vertebral collapse (² = 10.7, p < 0.01 and ² = 7.0, p < 0.01) and scoliosis (² = 10.9, p < 0.01 and ² = 11.1, p < 0.01) resulted significantly increased in CD patients as compared both to HS and NFA patients. In CD patients, the number of collapsed vertebral bodies was significantly correlated to age of disease onset (r = –0.63, p < 0.0001), disease duration (r = 0.33, p < 0.05) and urinary free cortisol levels at disease diagnosis (r = 0.72, p < 0.0001). The prevalence of cortical bone sclerosis was significantly increased in AOCD than in HS (² = 6.5, p < 0.01) and COCD (² = 7.7, p < 0.01) whereas that of trabecular bone rarefaction was significantly higher in COCD patients than in HS (² = 18.3, p < 0.0001), NFA (² = 14.2, p < 0.0001) and AOCD patients (² = 9.1, p < 0.01).Patients cured from CD have increased prevalence of spine damage, mostly when the disease developed before the completion of skeletal growth. Therefore, a periodical radiological follow-up of the skeleton and a specific treatment for the bone damage should be included in the management of patients with Cushing's syndrome.     

Metamorphosis of a Non-Functioning Pituitary Adenoma to Cushing's Disease

Silent pituitary adenomas occur in 25–40% of all clinically apparent pituitary tumours. However, the subsequent development of florid Cushing's disease in a patient with a previous non-functioning tumour is extremely rare. We describe a 47 year-old woman presenting initially with a large, invasive and recurrent, non-functioning pituitary tumour. Histopathologic study of the initial tissue did not stain for any hormones. Six years after the initial presentation, she manifested florid ACTH dependent Cushing's syndrome. A recurrent invasive pituitary macroadenoma necessitated a third transphenoidal surgery. The resected specimen, in this instance, revealed positive staining for ACTH, FSH, prolactin, and growth hormone on immunocytochemistry. An incomplete response to surgical, radiation and medical therapy necessitated a bilateral adrenalectomy to control the hypercortisolism, which resulted in remarkable clinical improvement. We also review five previous case reports from the revision literature of similar transformations from non-secreting pituitary adenomas to Cushing's disease. This subset of patients may represent yet another entity in the widening spectrum of Cushing's syndrome.     

Double Pituitary Lesions in Three Patients with Cushing's Disease

Double pituitary adenomas are rare in surgical specimens and the most common clinical feature in reported patients has been acromegaly. We report 3 cases of double pituitary lesions in patients who presented with Cushing's disease. In a 22-year-old man (case 1) with delayed puberty and low testosterone levels, mild hyperprolactinemia was diagnosed and treated with dopamine agonist therapy that reduced the prolactin (PRL) levels to normal. Over a 1-year period Cushing's disease developed gradually and was confirmed with classical endocrine testing. In a 27-year-old woman (case 2) who initially presented with severe depression and morbid obesity there was a gradual onset of Cushing's disease; initially she had minimally elevated serum PRL. In a 33-year-old woman (case 3) there was a 2-year history of Cushing's disease characterized by hirsutism, hypertension and weight gain; serum PRL was normal. Magnetic resonance imaging in all 3 patients revealed a microadenoma that was successfully removed by transsphenoidal pituitary surgery. Histology and immunocytochemistry in case 1 and case 3 revealed a corticotroph cell adenoma and a PRL cell adenoma in separate areas of the pituitary. In case 3 the PRL cell adenoma was silent but in case 1 the PRL cell adenoma may have been the cause of the mild hyperprolactinemia. In case 2 nodular corticotroph hyperplasia was the cause of Cushing's disease and a silent PRL cell adenoma was also identified.We conclude from these cases and a literature review that double pituitary lesions may occur in patients with Cushing's disease. The corticotroph part of the double lesion may consist of a corticotroph cell adenoma or, as reported in this study, of corticotroph nodular hyperplasia. The counterpart of the double lesion may consist either of a silent PRL cell adenoma or a functional PRL cell adenoma causing hyperprolactinemia.     

The Association of Cushing's Disease and Primary Empty Sella Turcica

The empty sella turcica is defined as the extension of the subarachnoid space toward the intrasellar region with displacement of the pituitary towards the posteroinferior wall. By autopsy studies, the incidence in the general population is around 20%. The association of Cushing's disease (CD) and empty sella has been infrequently reported. In our group, from a total of 68 patients with CD studied by magnetic resonance imaging (MRI), we found the presence of a primary empty sella syndrome (ESS) in 11 (16%). Of these, 9 had partial and 2 total ESS, and in four of them a microadenoma could be identified. Remission, ascertained by subnormal postoperative cortisol levels in blood and/or urine was obtained in 5 of 6 patients operated on by the transphenoidal route. Following surgery, 2 patients presented cerebrospinal fluid (CSF) leakage, 2 diabetes insipidus, and 2 some form of hypopituitarism, figures apparently higher than in non-ESS patients with CD. Ketoconazole was indicated as second line treatment in 2 patients and as primary therapy in 4, resulting in normal urinary free cortisol (UFC) values, with no complications. The relationship of ESS and CD is probably fortuitous given that the frequency of ESS in the general population is similar. Although in empty sella both surgery and radiotherapy seem to have greater risk of complications, surgery remains the first line treatment. Nevertheless, chronic treatment with ketoconazole could be a useful first choice, particularly when no adenoma is seen, or in those who have contraindications for surgery.     

Effect of the Serotonin Antagonists Ritanserin and Ketanserin in Cushing's Disease

Central serotonergic regulation couldhave a role in the course of pituitary-dependent Cushing's disease. We studied the effects of ritanserin and ketanserin, two related selective 5HT² receptor antagonists, in 11 patients with Cushing's disease. Treatment lasted from 1 month to 1 year (up to 4 years in one patient). Daily doses were 10—15 mg for ritanserin, and 40—80 mg for ketanserin. Since the two drugs share the same mechanism of action and no qualitative or quantitative differences in response to their administration were observed, the results were pooled together. Patients were assessed by clinical and hormonal evaluation. Urinary cortisol and ACTH were considered the parameters of interest. Short-term response: after 1 month, there was a signi~cant decrease of urinary cortisol from 781 (160) to 331 (215) nmol/d (P > 0.02) while ACTH was 9.8 (1.5) pmol/L baseline and again 8.8 (2.2) pmol/L at 1 month (P × NS). For 9 patients, hormonal parameters were available after 1 week of treatment. In this case, also ACTH levels were signi~cantly decreased (from 9.6 (1.7) to 5.2 (1.3) pmol/L; P > 0.01) together with urinary cortisol (from 781 (194) to 372 (165) nmol/d; > 0.01). Long-term response: in 3 patients, hormonal parameters failed to respond to serotonin receptor antagonists, which were thus discontinued. An improvement was recorded in the remaining 8 patients, that was prolonged in 3, and transient in 5. In 3 of these latter patients, a marked increase of ACTH was observed before treatment discontinuation. Ketanserin was given to 2 patients with Nelson's sydrome, with only transient ACTH decrease in one, and no changes in ACTH response to CRH after 1 month treatment in both cases. An inhibitory effect of ritanserin and ketanserin on ACTH and cortisol production in Cushing's disease appeared to be limited both in terms of duration of response and number of patients with a satisfactory outcome. However, the results may provide a better understanding of serotonergic modulation in Cushing's disease and lead to therapeutic developments.     

Nonsecretory IgD-Kappa Multiple Myeloma in a Patient with Gaucher's Disease

A patient with Gaucher's disease and non-secretory multiple myeloma is described. The presence of typical Gaucher and myeloma cells was confirmed by transmission and scanning electron microscopy. The immunological studies established the diagnosis of ‘non-secretory’ type of multiple myeloma.     

Repeated Remissions of Cushing's Disease Due to Recurrent Infarctions of an ACTH-Producing Pituitary Macroadenoma

Infarction of prolactin-secreting or growth hormone-secreting pituitary adenomas is not unusual. However, Infarction of ACTH-secreting adenomas has rarely been reported. Cyclical course of Cushing's syndrome alternating with adrenal insufficiency due to recurrent infarction of an ACTH-secreting pituitary adenoma has not been reported. We report here a 20-year-old lady who presented with florid signs of Cushing's syndrome but was found to have adrenal insufficiency on biochemical evaluation. Magnetic resonance imaging (MRI) of the pituitary gland showed that she had infarction of an ACTH-secreting macroadenoma. Over the next 6 years, her disease ran a cyclical course characterized by periods of hypercortisolism alternating with adrenal insufficiency due to repeated episodes of infarctions of the ACTH-secreting pituitary macroadenoma with corresponding changes in the pituitary adenoma on serial MRIs. The case alerts clinicians to this possibility when a patient presents with clinical picture of Cushing's syndrome but has adrenal insufficiency on biochemical testing. It also suggests that silent or subclinical infarction of pituitary adenomas is not uncommon and is probably under diagnosed.     

Recurrence of Cushing's Disease Preceded by the Reappearance of ACTH and Cortisol Responses to Desmopressin Test

At present no single test is considered of absolute value in identifying patients successfully operated for Cushing's disease who are at risk for recurrence. The present report describes the first two patients in whom ACTH/cortisol abnormal responses to desmopressin disappeared after cure and then clearly reappeared during long-term follow-up several months before the clinical and hormonal features of hypercortisolism became manifest. The case histories of 2 young women are reported. The diagnosis of Cushing's disease was made on the basis of clinical features and standard hormonal criteria. Both patients, showing abnormal ACTH/cortisol rises after desmopressin test, underwent pituitary adenomectomy by transsphenoidal surgery and after operation plasma ACTH and serum cortisol levels were 0.2 and 0.4 pmol/l and 56 and 32 nmol/l, respectively. During the follow-up both patients underwent desmopressin (10 μg iv), ovine CRH (1 μg/kg iv) and 1 mg dexamethasone tests at 1, 6, 12, 24 months after surgery. In these two cases the ACTH/cortisol response to desmopressin normalized following pituitary adenomectomy, concomitantly with the normalization of all the other clinical and hormonal parameters. Subsequently abnormal rises after the synthetic AVP analogue administration appeared: paradoxical ACTH/cortisol increments after desmopressin occurred 24 and 6 months before any other hormonal or clinical sign of recurrence of hypercortisolism. As desmopressin may be able to stimulate ACTH/cortisol release in Cushing's disease, but not in normal subjects, we suggest that it can have a role in early identifying successfully operated Cushing's patients at risk for recurrence.     

库欣病术后预后相关因素

库欣病经蝶窦显微外科垂体腺瘤切除术后预后相关因素包括:肿瘤分级、术中发现、术后病理、术后血清皮质醇水平、血浆促肾上腺皮质激素(ACTH)水平等.尽管一些指标能够较好地预示手术失败或术后缓解,但目前无一指标是完美的,应长期监测患者下丘脑-垂体-肾上腺轴功能.本文综述了与库欣病经蝶垂体瘤术后预后相关的因素.     

Cushing's syndrome in a clinic population with diabetes

Background: A recent report has suggested that occult Cushing’s syndrome (CS) may be present in a significant number of patients with type 2 diabetes mellitus. The aim of this study was to determine whether any patients in our clinic population with diabetes had this condition. Methods: One hundred and seventy‐one consecutive overweight attendees at the diabetic clinic were enrolled in a study to assess the presence of occult CS. The initial screen was with the 1 mg overnight dexamethasone suppression test and follow‐up testing, where indicated was with a 24 h collection for urine‐free cortisol. Results: Thirty‐one of 171 patients had a positive result from the overnight dexamethasone suppression test. Follow‐up testing with 24 h urine‐free cortisol reduced the number of patients with positive results to 3. Two of these were shown to have alcoholic pseudo‐CS. The third patient has had several high urine‐free cortisol results, in the presence of normal scans of pituitary and adrenals. He has no stigmata of CS and is being observed. Conclusion: Based on the results of our study, there would appear to be little value in screening type 2 diabetics for CS, in the absence of clinical suspicion.     

生长抑素类似物治疗库欣病的研究进展

垂体促肾上腺皮质激素(ACTH)瘤表达生长抑素受体(SSTR),主要亚型为SSTR2和SSTR5.SSTR2表达可因皮质醇作用而下调.临床上常用的生长抑素类似物奥曲肽和兰瑞肽主要作用于SSTR2,对库欣病无明显治疗作用.帕瑞肽是作用于SSTR多亚型的新型生长抑素类似物,基础和临床研究证实其可有效降低库欣病患者血、尿皮质醇,改善症状,为库欣病带来新的治疗前景.     

Nuclear Hypersegmentation in the Myeloma Cells of a Patient with Multiple Myeloma

A patient with multiple myeloma in whom the bone marrow plasmablasts showed extensive lobulation is described. In addition to numerous lobes, some of the nuclei had a cerebriform appearance, similar to that observed in Sezary cells. The possible relation of this phenomenon to the expression of the altered function of the malignant cells is discussed.     

Extreme Potassium Loss in a Patient with Severe Graft Versus Host Disease

A 19-year-old male, suffering from post-hepatitis aplastic anaemia, was transplanted with bone marrow cells from his HLA-identical, MLC non-reactive brother. Haematological recovery ensued, but the patient also developed grade IV graft-versus-host disease (GVHD). In addition to involvement of skin, liver and gut, the kidney seemed affected by GVHD since the patient had hypokalaemia and severe hyperkaluria. Other causes of urinary potassium loss were excluded. The amount of potassium loss correlated well with the severity of the GVH-reaction. Although coagulation disorders prohibited a kidney biopsy, the clinical course suggested GVHD to be the cause of the urinary potassium loss.     

Multiple Gastric Carcinoids in a Patient with a History of Primary Hyperparathyroidism

A 66-year-old man with a past history of hyperparathyroidism was evaluated for chronic epigastric pain. An upper gastrointestinal x-ray examination revealed the presence of polypoid filling defects and endoscopy-polypectomy eventually proved these to be gastric carcinoids.