库欣综合征所致精神症状的机制

库欣综合征是由长期过量皮质醇所产生的一组症候群.患者体内高浓度的糖皮质激素可通过损伤神经细胞、诱导神经细胞凋亡、抑制神经再生和调节突触可塑性等多种方式破坏大脑的结构及功能,产生抑郁及认知障碍等精神症状,并可能伴随有海马等结构的萎缩.手术、米非司酮等药物治疗可使精神症状得到改善.     

Fine structure of adrenal adenomata causing Cushing's syndrome

Summary Adenomata taken from nine patients with Cushing's syndrome were observed by electron microscopy. Agranular endoplasmic reticulum was prominently developed in all cases, occasionally fine dotty granules were observed in the tubules of agranular endoplasmic reticulum.Mitochondria showed a wide variety of changes in size, shape and internal structure, and somtimes contained electron dense droplets in their matrix. Mitochondria resembling those in the normal zona fasciculata intermingled with pathologically altered ones, suggesting that the adenomata which caused Cushing's syndrome were derived from the zona fasciculata.Fibrous structures were seen in the cytoplasm in one case. It is proposed that all of the changes in cellular organelles of the adenoma cells are correlated with increased secretory activity.     

Primary thymic carcinoid with Cushing's syndrome

Summary In a 52-year-old Caucasian man osteopoikilosis had been misdiagnosed roentgenologically 2 years before his death. Gradually he developed Cushing's syndrome and ultimately superior vena caval obstruction. At autopsy a primary thymic carcinoid with extensive osteoblastic bone metastasis was found. Immunohistochemically the tumor was shown to be positive for adrenocorticotropic hormone (ACTH), cytokeratin (KL1), neuron-specific enolase, synaptophysin, chromogranin and glucagon. Remarkably the tumour was negative for serotonin despite high urinary hydroxyindolacetic acid levels. Bilateral hyperplasia of the adrenal cortex was found. The adenohypophysis showed a considerable reduction of ACTH-producing cells and numerous Crooke's cells with a characteristic immunohistochemical pattern.     

库欣综合征所致高凝状态的研究进展

库欣综合征是高皮质醇血症所致的临床症候群,该病患者常合并高凝状态,其动静脉血栓事件、心血管病发生率乃至病死率均高于普通人群。本文将介绍库欣综合征高凝状态的病理生理机制,并对临床上预防性使用抗凝药物提供指导。     

Corticotropin-producing pulmonary gangliocytic paraganglioma associated with Cushing's syndrome

Gangliocytic paraganglioma (GP) is an unusual tumor in the wide spectrum of neuroendocrine neoplasms. The biologic behavior and histogenesis of this tumor is uncertain because, despite its benign histologic features, there have been reports of metastases to regional lymph nodes and distant metastases. Although most of these tumors have been reported in the duodenum, examples of GP arising in extra-ampullary sites have been well documented. Herein, we report the case of a lung GP corticotropin producing and presenting as Cushing's syndrome. After removal of the tumor, there was a significant drop in cortisol and corticotropin levels. To our knowledge, this is the first report of a GP causing Cushing's syndrome.     

Adrenal black adenoma associated with preclinical Cushing's syndrome

A black adenoma of the adrenal gland was laparoscopically removed from a 60-year-old man who presented with severe hypertension. Although laboratory findings were indicative of preclinical Cushing's syndrome, there were no clinical features characteristic of Cushing's syndrome. Microscopically, the tumor showed a proliferation of polygonal cells containing numerous brown-pigmented granules. Special staining studies revealed these granules to be lipofuscin. Electron microscopy also identified lipofuscin and lysosomes in these cells. The morphological appearance of the tumor and the adjacent atrophic non-tumorous adrenal cortex supports the assumption that the black adenoma caused preclinical Cushing's syndrome.     

The effect of saralasin (1-Sar-8-Ala-Angiotensin II) on blood pressure in patients with cushing's syndrome

Summary To investigate the role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome two patients with hypercorticism were infused with 20 mg saralasin (1-sar-8-alaangiotensin II) over a period of 30 minutes under constant blood pressure control. In addition, one patient with primary aldosteronism, an established form of mineralocorticoid hypertension, served as control.Neither in the two patients with Cushing's syndrome nor in the patient with primary aldosteronism could a blood pressure lowering effect of saralasin be observed.In the two patients with hypercorticism both renin activity and plasma aldosterone increased during saralasin infusion. The patient with primary aldosteronism only showed a weak increase in plasma aldosterone concentration.These results seem to exclude an important role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome. The unresponsiveness of elevated blood pressure to saralasin in the two patients with hypercorticism and in the patient with primary aldosteronism indirectly supports the assumption that in patients with Cushing's syndrome increased mineralocorticoid activity may be the main factor in the pathogenesis of hypertension.     

Steroid biosynthesis inhibitors in Cushing's syndrome

Conclusions About one-third of all patients with Cushing's syndrome cannot be cured by surgery (at the pituitary or adrenal level) or radiation therapy and are therefore candidates for medical treatment. As a conservative therapeutic approach to lower hypercortisolism, the use of steroid biosynthesis blocking substances has the greatest importance. Trilostane, an inhibitor of the adrenal 3-hydroxysteroid dehydrogenase 5,4-isomerase system, has been studied in only a few patients with Cushing's syndrome and was not potent enough to normalize hypercortisolism, especially in patients with pituitary-dependent Cushing's disease.Aminoglutethimide, predominantly blocking side-chain cleavage, normalized elevated serum or urinary cortisol levels in only a minority of patients with Cushing's disease and showed adverse reactions in the majority.Metyrapone, a strong inhibitor of adrenal 11-hydroxylase activity, has only an insufficient blocking effect on elevated cortisol levels in some patients with various forms of Cushing's syndrome and shows side effects in a significant number of patients.Ketoconazole in vitro blocks predominantly adrenal 17,20-desmolase activity and to a lesser extent 17- and 11-hydroxylase activity. Therefore the substance in vivo more markedly suppresses serum androgen levels (dehydroepiandrosterone sulfate, androstenedione, testosterone) than cortisol. However, clinical data from several groups show that the administration of ketoconazole normalizes the urinary excretion of cortisol in the mean in about 70% of patients with Cushing's disease. Furthermore, the antimycotic drug was effective in many patients with a benign primary adrenal form of Cushing's syndrome, in about 50% of patients with ectopic ACTH syndrome, but rarely in patients with adrenocortical carcinoma. The main side effect of ketoconazole is liver toxicity, in about 10% of all cases.Etomidate has strong inhibiting properties on adrenal 11-hydroxylase activity and in vivo is the most potent substance to normalize hypercortisolism. However, its widespread use is prevented by the necessity of intravenous administration.Mitotane inhibits various pathways of adrenal steroid biosynthesis, but its main effect is a cytolytic effect especially on adrenocortical cells. It is therefore a special cytostatic drug for patients with adrenocortical carcinoma. High doses of the substance lower or normalize elevated cortisol parameters in the majority of these patients, but objective tumor regression has been documented in only in few cases.Abbreviation ACTH adrenocortropic hormone     

Urinary free cortisol versus 17-hydroxycorticosteroids a comparative study of their diagnostic value in Cushing's syndrome

Summary We evaluated the usefulness of the basal urinary 24-h excretion rates of free cortisol versus 17-hydroxycorticosteroids in the diagnosis of Cushing's syndrome. On an outpatient basis, both urinary free cortisol and 17-hydroxycorticosteroids levels were determined in 48 patients with Cushing's syndrome, as well as in 95 obese and 94 healthy control persons of normal weight. Determination of the urinary free cortisol content allowed a clear-cut distinction between the patients with hypercortisolism and the controls, resulting in a sensitivity of 100% and specificity of 98% for the diagnosis of Cushing's syndrome. The diagnostic accuracy of urinary free cortisol was distinctly superior to that of 17-hydroxycorticosteroids, which showed a wide overlap of values between the groups, with a sensitivity of 73% and a specificity of 94%. In conclusion, the measurement of basal urinary free cortisol provided an excellent diagnostic sensitivity and specificity in the assessment of adrenocortical function. This simple and accurate test thus seems to be particularly useful in the outpatient evaluation of patients with suspected Cushing's syndrome.Abbreviations 17-OHCS 17-hydroxycorticosteroids - ACTH adrenocorticotropic hormone - BMI body-mass index - UFC urinary free cortisol     

Low-dose dexamethasone suppression of urinary free cortisol in the differential diagnosis between Cushing's syndrome and obesity

Summary Urinary free cortisol (UFC) was measured in the basal state and on 2nd day of the low-dose dexamethasone (2 mg daily for 2 days) suppression test (LDDT) in 182 subjects. At first examination the results were in good agreement with the definite diagnosis in 21 of 27 patients with Cushing's syndrome (CS) and in 145 out of 155 obese subjects. In two obese subjects the basal UFC was increased and the response to the test insufficient. At re-examination their laboratory findings became normal. In 14 subjects the basal UFC was increased but the response to the test was normal. With nine of them, repeated examinations were performed over a period of 1–7 years. Six subjects progressed into obvious CS, while in two hypercortisolism spontaneously regressed and in one it remained unchanged. The combination of elevated basal UFC with a normal suppressibility during the LDDT is considered a borderline adrenocortical impairment.Abbreviations CPB competitive protein binding method - CS Cushing's syndrome - LDDT low-dose dexamethasone test - RIA radioimmunoassay - UFC urinary free cortisol     

髓过氧化物酶(MPO)在妊高征发病中的作用

目的本文旨在探讨髓过氧化物酶在妊高征发病中的作用。方法采用分光光度计比色法检测胎盘组织中中性粒细胞髓过氧化物酶(MPO)活性。结果重度妊高征组胎盘组织MPO含量显著高于中度妊高征组(P<0.05);重度妊高征组胎盘组织MPO含量显著高于正常组(P<0.05);中度妊高征组胎盘组织MPO含量与正常组相比较没有显著性差异(P>0.05)。结论重度妊高征妇女胎盘组织髓过氧化物酶含量较正常孕妇相比增高,差异有显著性,支持妊高征发病的中性粒细胞活化导致的内皮细胞损伤学说。     

Electron microscopical morphometry of well-differentiated and undifferentiated ACTH secreting adenomas in Cushing's disease and Nelson's syndrome

Summary Adrenocorticotrophic hormone (ACTH)-secreting adenomas of patients with Cushing's disease (undifferentiated and well-differentiated ACTH-cell adenomas) were studied ultrastructurally and analysed morphometrically by a computer-supported quantitative image-analysing system. They were compared with identically prepared ACTH tumours (undifferentiated and well-differentiated ACTH-cell adenomas) of pituitaries from bilateral adrenalectomised patients with Nelson's syndrome. The aim of our study was to look for significant differences in ultrastructure and to evaluate these findings statistically regarding adenoma types and clinical syndromes. Clinical syndromes aside, more secretory granules and larger-sized prosecretory granules were measured in the well-differentiated ACTH-cell adenomas. The undifferentiated adenomas showed a greater content of nucleoli and prosecretory granules. Within the adenoma types, comparison of well-differentiated ACTH-cell adenomas showed that the clinical group of Cushing's disease contained larger areas of cytofilaments, whereas the clinical group of Nelson's syndrome had a larger tumour size and more lysosomes. Comparing the undifferentiated adenomas of both clinical groups the adenomas in Cushing's disease contained larger nuclei and more lysosomes, whereas the adenomas in Nelson's syndrome were larger in tumour size and contained larger prosecretory granules. Comparison of well-differentiated and undifferentiated adenomas in Cushing's disease showed more secretory granules and bigger prosecretory granules in well-differentiated adenomas whereas in undifferentiated adenomas the total area of the nuclei is larger, the nucleoli increase in number and size and the lysosomes are more frequent. Comparison of well-differentiated and undifferentiated adenomas in Nelson's syndrome demonstrated more lysosomes in well-differentiated adenomas and a larger total area of the nuclei in undifferentiated adenomas. The differences between the well-differentiated adenomas (mainly more secretory granules and larger prosecretory granules) and undifferentiated adenomas (mainly more and larger nuclei and nucleoli and more prosecretory granules) prove the clear separability between the adenoma types, not demonstrated in the literature up to now. The significant differences between adenomas in Cushing's disease (mainly more cytofilaments) and Nelson's syndrome (mainly more ribosomes and larger prosecretory granules) may be interpreted as different cell reactions due to the hypercortisolism present in Cushing's disease and lacking in Nelson's syndrome following adrenalectomy. Despite the fact that both clinical syndromes are based on the same adenoma types, indistinguishable by light microscopy, significant morphometrical findings in ultrastructure allow a clear discrimination of both clinical types.Dedicated to Prof. Gerhard Seifert on the occasion of his 70th birthdayPresented at the 5th European Workshop on Pituitary Adenomas, Venice, March 1991     

线粒体钙在妊高征发病中的作用

目的本文旨在探讨线粒体钙。方法线粒体钙采用火焰原子吸收法测定。结果重度妊高征组胎盘组织线粒休Ca2 含量显著高于中度妊高征组(P<0.05);重度妊高征组胎盘组织线粒休Ca2 含量显著高于正常组(P<0.05);中度妊高征组胎盘组织线粒休Ca2 含量与正常组相比较没有显著性差异(P>0.05)。结论重度妊高征妇女胎盘组织线粒体钙含量高于正常孕妇,提示妊高征发病晚期患者体内存在导致能量代谢异常的因素,并不排除线粒体钙参与了妊高征患者胎盘微小动脉痉挛的病理生理改变。     

高血压病患者微血管改变与血管内皮细胞损伤关系及开搏通的影响

探讨不同期高血压病(EH)患者微血管改变与血管内皮细胞(VEC)损伤、功能障碍的关系及开搏通(CPT)对其的影响。方法对Ⅰ期、Ⅱ期及Ⅲ期EH患者各20例应用CPT口服治疗10日 ,观察治疗前后球结膜微血管、血浆一氧化氮(NO)、内皮素(ET)浓度及循环内皮细胞(CEC)计数的变化 ,并与正常对照组(NC组 ,n=23)比较。结果治疗前 ,66.67 %的EH患者出现球结膜缺血区 ,明显多于NC组(P<0.001)。EH患者的微动脉与微静脉管径比(A/V)、NO低于NC组(P均<0.001) ,而ET和CEC则高于后者(P<0.05) ,且这种变化随病情严重而加重。EH患者的A/V与NO呈正相关(r=0.6533,P<0.01)、并分别与ET和CEC呈负相关(r= -0.5607,P<0.01;r= -0.7182,P<0.01)。经CPT治疗后 ,EH患者的血压降低(P<0.001),A/V和NO增大(P<0.001和P<0.01) ,ET和CEC下降(P<0.05和P<0.01) ,Ⅰ、Ⅱ期患者的缺血区减少(P<0.05～0.01)。结论EH的微血管改变与VEC损伤关系密切。CPT可以减少EH患者的缺血区、扩张其微动脉 ,这与CPT对VEC结构和功能的保护作用有关     

Increased activity of the Na-K-ATPase in red cell-ghosts of patients with Cushing's Syndrome: Possible significance for the pathogenesis of glucocorticoid-induced hypertension

Summary The Na-K-ATPase activity of erythrocyte ghosts was increased in 6 patients with Cushing's syndrome compared with 28 control subjects (0.986±0.291 versus 0.259±0.1 µM P_i·h^–1·mg^–1,p<0.001). Ouabain insensitive Mg-ATPase activity was similar in both groups. These data support the concept of an activation of the Na-pump in patients with glucocorticoid excess.     

Ultrastructure of pigment in adrenocortical pigmented adenomas of Cushing's syndrome and in non-functioning pigmented nodules with respect to tissue steroid analyses

Summary Ultrastructural and morphometrical analysis of brown pigment in pigmented (black) and non-pigmented adrenocortical adenomas of Cushing's syndrome and non-functioning pigmented adrenocortical nodules was performed in reference to tissue concentrations and in vitro production of steroids by the adenoma tissue. Pigment in pigmented adenomas was of membrane-bound lysosomal nature, while that of pigmented nodules contained membrane-unbound droplets of lipoid character. The morphometrical study showed little difference among individual adenomas. There was no difference between pigmented and non-pigmented adenomas in the amount of production and tissue concentrations of steroids. The steroid concentrations in a pigmented nodule were lower than those in an adenoma of Cushing's syndrome, but not significantly. Discussion is focused on the difference of pigment of lysosomal nature and of lipoid peroxidation.This study was in part supported by a grant from the Ministry of Health and Welfare Disorders of adrenal hormone Research Committee, Japan     

Adrenocorticotropin-independent unilateral adrenocortical hyperplasia with Cushing's syndrome: Immunohistochemical studies of steroidogenic enzymes, ultrastructural examination and a review of the literature

A 60-year-old woman presented with a history of palpitations, headaches and severe hypertension, which was resistant to hypotensive agents. She had a 2-year history of obesity and a moon face. Her plasma adrenocorticotropic hormone level was below the limits of detection and did not respond to corticotropin-releasing hormone. Urinary-free cortisol was elevated and the circadian rhythm of serum cortisol level had completely disappeared. Imaging analysis demonstrated a unilaterally functioning mass in the left adrenal gland. Serum cortisol level in the left adrenal vein was elevated. The resected adrenal mass measured 4 x 3.5 x 2.5 cm, and ranged from yellow to tan in color. The adrenal cortex adjacent to the nodule did not demonstrate cortical atrophy. The mass was well circumscribed but not encapsulated, and consisted of multiple cortical nodules. These nodules were composed predominantly of clear cortical cells, and partly of compact cortical cells. Immunoreactivity of steroidogenic enzymes including cholesterol side-chain-cleavage P450, 3beta-hydroxysteroid dehydrogenase, 21-hydroxylase cytochrome P450, 11beta-hydroxylase cytochrome P450 and 17alpha-hydroxylase cytochrome P450 was marked in cortical nodules, but minimal in non-nodular cortex. Ultrastructural examination of nodular cortical cells also demonstrated well-developed mitochondria and smooth endoplasmic reticulum, consistent with elevated steroidogenesis in these cells.     

Captopril before and after spironolactone therapy in primary aldosteronism

Summary In three patients with primary aldosteronism, the acute effect of a single dose of captopril on the elevated mean arterial blood pressure (MAP) was studied before and after 4 weeks of treatment with spironolactone. Before spironolactone therapy, captopril did not cause any drop in MAP. Four weeks later, after an oral daily dose of 400 mg spironolactone, MAP was still elevated in all three patients, though electrolyte abnormalities were fully corrected. Since plasma renin activity (PRA) was increased to values above the normal range, the acute effect of captopril on MAP was tested again. A single dose of 25 mg captopril then caused a fall in MAP to normal. These data reveal the conversion from a renin-independent to a renindependent kind of hypertension after spironolactone therapy in three patients with primary aldosteronism syndrome. This might be of pathogenetic and therapeutic interest.Abbreviations CT Computed tomography - MAP Mean arterial pressure - PA Plasma aldosterone - PRA Plasma renin activity     

Cushing's syndrome due to a large adrenocortical adenoma with histological features simulating ACTH-independent macronodular adrenocortical hyperplasia

A 53-year-old woman presented with Cushing's syndrome resulting from an adrenocortical adenoma, 6.5 cm in diameter and 75 g in weight, which is larger than usual. Endocrinological data of this patient showed adrenocorticotropin (ACTH)-independent hypercortisolemia. A computed tomography scan of the adrenal glands revealed a single large and well-encapsulated tumor with an irregularly shaped area of calcification and loss of parenchyma on the left adrenal. The right adrenal gland was atrophic. Laparoscopic removal of the left adrenal tumor was performed. The tumor was lobulated and clearly encapsulated, and the non-neoplastic area of the left adrenal was atrophic without any nodularity. The histological analysis confirmed the diagnosis of adrenal adenoma. In addition, this adenoma displayed histopathological features in common with ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), including clear cell predominance, a pattern of small compact cell nests in clear cell areas, and very long cord-like arrangement of small compact cells. In AIMAH, adrenals are extremely enlarged and are more massive than in any other subtype of Cushing's syndrome. The fact that the present adrenocortical adenoma was larger than those typical adenomas of Cushing's syndrome may reflect an AIMAH-type cellular composition of clear cell predominance and small compact cell nests.     

Cushing's Syndrome Secondary to Olfactory Neuroblastoma

A case of olfactory neuroblastoma in a 36-year-old woman who presented with florid Cushing's syndrome is reported. A nasal polyp, which proved to be an olfactory neuroblastoma, was resected. The procedure was followed by complete remission from the endocrinologic abnormalities. Postoperatively, the patient was well for 5 years until recurrence of both Cushing's syndrome and the nasal polyp was noted. Following combined transnasal-transcranial resection of the tumor, which extended into the anterior cranial fossa, the patient again experienced complete remission of Cushing's syndrome. Immunohistochemistry showed the tumor to be positive for neuron-specific enolase, synaptophysin, chromogran-in, adrenocorticotropic hormone, (J-endorphin, and S-100 protein. Electron microscopy revealed neuritic processes containing microtubules and neurosecretory granules. This is the first reported case of Cushing's syndrome secondary to olfactory neuroblastoma.