Cushing综合征的药物治疗进展

Cushing综合征是因下丘脑—垂体—肾上腺轴调控失常而致肾上腺分泌过多糖皮质激素所致病症的总和,目前的药物治疗靶点包括控制下丘脑—垂体的促肾上腺皮质激素的合成和分泌、阻断肾上腺异常表达受体、抑制肾上腺糖皮质激素的合成和分泌,以及阻断外周糖皮质激素的效应。近年来,随着研究的深入,循证医学为传统的治疗方法提供了临床证据,越来越多的潜在药物靶点被发现,本文就Cushing综合征的药物治疗进展作相关综述。     

精神心理障碍及下丘脑-垂体-肾上腺轴对冠心病的影响

下丘脑-垂体-肾上腺轴是神经内分泌系统的重要组成部分,下丘脑-垂体-肾上腺轴及其产物是参与中枢神经系统调节免疫系统的主要枢纽。最近越来越多证据表明下丘脑-垂体-肾上腺轴功能失调可能是精神心理障碍引起冠心病的主导机制。现综述精神心理障碍中下丘脑-垂体-肾上腺轴功能失调对冠心病的影响及相关机制的研究进展,以期在临床工作中应对这类多学科交叉疾病,提供新的思路。     

氨基导眠能对下丘脑—垂体—肾上腺轴功能的影响

氨基导眠能(aminoglutethimide,AG)系在六十年代初合成并用于治疗癫痫,后发现此药具有抑制肾上腺皮质激素合成的作用而用于柯兴综合征的治疗。为了研究AG对下丘脑-垂体-肾上腺轴功能的影响,我们检测了柯兴病、单纯肥胖(肥胖)、垂体前叶功能减低(垂低)患者和正常人在服固定剂量AG后下丘脑-垂体-肾上腺轴功能的变化,结果报告如下。     

急性脑血管疾病血甲状腺激素,儿茶酚胺,皮质醇测定及其临床意义

急性脑血管疾病时,内环境(包括神经内分泌系统)也发生一系列复杂的变化。本实验旨在探讨该病急性期下丘脑-垂体-肾上腺轴和下丘脑-垂体-甲状腺轴的功能状态的变化在临床上的意义。     

2型糖尿病与下丘脑-垂体-肾上腺轴

2型糖尿病的发生往往由于胰岛素的绝对和(或)相对缺乏,此外还在一定程度上和下丘脑-垂体-肾上腺轴功能改变密切相关。2型糖尿病患者随着下丘脑-垂体-肾上腺轴的改变导致糖皮质激素水平增高,加重了糖代谢和脂代谢紊乱,使糖尿病患者的病情恶化,最终促使糖尿病并发症的发生。     

CRH和赖氨酸血管加压素刺激试验在诊断继发于下丘脑或垂体疾病的肾上腺皮质功能减退中的应用

促肾上腺皮质激素释放激素(CRH)刺激试验可作为诊断Cushing综合征的一个有价值的手段,特别是在鉴别ACTH依赖性的和非依赖性的Cushing综合征以及在评估Cushing病患者垂体微腺瘤切除的效果中有重要意义。作者研究继发于垂体或下丘脑疾病的继发性肾上腺皮质功能减退患者的ACTH对CRH和赖氨酸血管加压素(LVP)的反应。 病人和方法 继发于下丘脑或垂体疾病的肾上腺皮质功能减退患者10例(男6例,女4例,年龄22～56岁),临床诊断依据为血浆基础皮质醇和ACTH水平低于正常以及对胰岛素诱导的低血糖或甲吡酮     

松果腺褪黑素对下丘脑-垂体-肾上腺轴的调节作用

松果腺褪黑素对多种不同功能状态下的下丘脑 垂体 肾上腺轴都有一定调节作用。其机制不仅在于直接与下丘脑 垂体 肾上腺轴上的褪黑素受体结合刺激激素释放 ,并影响糖皮质激素受体的功能 ,而且与五羟色胺、内阿片肽等神经递质、调质相互联系 ;且下丘脑 垂体 肾上腺轴对松果腺褪黑素存在反馈作用。这种调节的广泛性使褪黑素用于内分泌、免疫、精神神经系统疾患的治疗成为可能。     

库兴氏综合征诊断中的若干问题

自1932年Cushing氏系统地描述本病以来,人们对库兴氏综合征(以下简称库兴氏征)的认识逐渐深刻。本综合征可见于垂体瘤引起的肾上腺增生、下丘脑——垂体功能障碍所致的肾上腺皮质增生及肾上腺皮质的肿     

肝硬变病人的垂体肾上腺轴机能

血浆皮质醇水平的变化反映肾上腺皮质的分泌和组织器官对皮质醇的降解转化作用。生理状态下下丘脑-垂体-肾上腺轴控制皮质醇的合成和分泌。血浆皮质醇浓度升高抑制垂体促皮质素(ACTH)的释放。起激素自身负反馈控制作用。生理状态下下丘脑-垂体-肾上腺轴调节控制作用使昼夜间的血浆皮质醇水平呈节律性变化。肝脏是糖类皮质素作用的主要靶器官和降解转化场所。我们曾报告了各种肝病时血浆皮质醇的变化,本文又进一步观察了肝硬变病人血浆皮质醇昼     

催乳素释放肽的研究进展

催乳素释放肽是新近发现的一种神经肽,它在下丘脑、延髓、外周组织中都有分布.研究显示它在调节催乳素和生长激素的释放、调节下丘脑-垂体-性腺轴、下丘脑-垂体-肾上腺轴及睡眠、摄食等方面具有广泛的作用.本文综述了催乳素释放肽的基因、结构、组织分布和生物学功能.     

Subclinical Cushing's disease: presentation of three cases and critical review

Unlike subclinical Cushing's disease, adrenal subclinical Cushing's syndrome is widely recognized. It is defined as an autonomous cortisol hyperproduction of mild intensity not causing specific clinical signs, but detectable biochemically as derangements of the hypothalamic-pituitary-adrenal axis function. Although Cushing's disease accounts for the majority of hypercortisolism states, subclinical Cushing's disease has been rarely reported. Three cases of subclinical Cushing's disease due to pituitary corticotrophic macroadenomas, confirmed by immunohistochemistry, are presented in order to underscore its recognition by clinical endocrinologists and to emphasize a diagnostic evaluation of hypercortisolism in all cases of pituitary adenomas.     

The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment

Pregnancy dramatically affects the hypothalamic-pituitary-adrenal axis leading to increased circulating cortisol and ACTH levels during gestation, reaching values in the range seen in Cushing's syndrome (CS). The cause(s) of increased ACTH may include placental synthesis and release of biologically active CRH and ACTH, pituitary desensitization to cortisol feedback, or enhanced pituitary responses to corticotropin-releasing factors. In this context, challenges in diagnosis and management of disorders of the hypothalamic-pituitary-adrenal axis in pregnancy are discussed. CS in pregnancy is uncommon and is associated with fetal morbidity and mortality. The diagnosis may be missed because of overlapping clinical and biochemical features in pregnancy. The proportion of patients with primary adrenal causes of CS is increased in pregnancy. CRH stimulation testing and inferior petrosal sinus sampling can identify patients with Cushing's disease. Surgery is a safe option for treatment in the second trimester; otherwise medical therapy may be used. Women with known adrenal insufficiency that is appropriately treated can expect to have uneventful pregnancies. Whereas a fetal/placental source of cortisol may mitigate crisis during gestation, unrecognized adrenal insufficiency may lead to maternal or fetal demise either during gestation or in the puerperium. Appropriate treatment and management of labor are reviewed.     

Long term bromocriptine therapy in Cushing's disease

Recently, bromocriptine has been successfully introduced as medical therapy for the pituitary hypersecreting syndromes of hyperprolactinemia and acromegaly. Subsequently, an inhibitory effect on ACTH secretion was reported using bromocriptine in Cushing's disease. While most studies have focused on the acute response to bromocriptine, few have investigated the response to chronic therapy with this agent. In this report, we describe a patient with Cushing's disease in whom an acute inhibition of ACTH and cortisol was demonstrated following bromocriptine and in whom the long term administration of bromocriptine as the sole therapy produced a transient beneficial response. Further pharmacologic testing suggested this inhibitory effect on the hypothalamic-pituitary-adrenal axis was mediated through dopaminergic stimulation.     

RU486 对正常人和库欣综合征患者垂体-肾上腺轴的影响及其临床应用

本文观察了１０例正常人和１４例库欣综合征患者垂体肾上腺轴在单次口服ＲＵ４８６４ｍｇ／ｋｇ后的反应。正常人在８ｐｍ口服ＲＵ４８６后连续２天８Ａｍ的血促肾上腺皮质激素（ＡＣＴＨ）和皮质醇（Ｆ）均明显升高（Ｐ＜０．０１，Ｐ＜０．００１），服药后第一天２４ｈ尿Ｆ亦明显升高（Ｐ＜０．００１）。库欣综合征组服药后连续观察２天上述激素水平无明显改变。正常组服药后连续２天的血Ｆ，ＡＣＴＨ及２４ｈ尿Ｆ较服药前所增加的百分比均明显高于库欣综合征组（Ｐ＜０．０５）。正常人和库欣综合征患者的垂体肾上腺轴对ＲＵ４８６有明显不同的反应。我们认为一次法ＲＵ４８６激发试验诊断库欣综合征优于小剂量地塞米松抑制试验，可能有临床应用价值。     

Cushing's syndrome

The clinical characteristics and current concepts of pathophysiology of Cushing's syndrome have been reviewed. The specific type of pituitary or ectopic ACTH-dependent and ACTH-independent Cushing's syndrome and the underlying pathology can be determined biochemically and with the aid of anatomic localization procedures. Several approaches are available for treating pituitary ACTH-dependent Cushing's syndrome, but transsphenoidal pituitary microsurgery is the ideal type, with remission of the disease being observed in 80 to 90% of cases. When successful, pituitary microsurgery is followed by preservation of normal pituitary function and restoration of normal hypothalamic-pituitary-adrenal function within 6 to 12 months postoperatively. Medical therapy of Cushing's disease includes drugs that inhibit CRH-ACTH secretion, such as cyproheptadine and bromocriptine, and agents that inhibit cortisol synthesis, such as aminoglutethimide, metyrapone, ketoconazole, and mitotane, or that block the action of cortisol at the glucocorticoid receptor level, such as RU-485. With the exception of mitotane, which has adrenalytic effects, the action of the other pharmacologic agents is promptly reversed when treatment is discontinued. Thus, drug therapy is effective only as temporary treatment for Cushing's syndrome when surgical approaches are contraindicated or when attempts are made to improve the patient's clinical and metabolic status in preparation for surgery. Mitotane is effective in extending survival of patients with adrenal carcinoma, particularly when it is administered early as adjuvant therapy or when it is combined with repeated debulking resection of recurrent tumor. The toxicity associated with mitotane administration limits the use of larger and probably more effective doses in these patients. The synthesis of more specific cytochrome P-450 enzyme inhibitors and of mitotane analogues with more limited toxicity may ultimately provide more effective tools in the pharmacologic management of Cushing's syndrome.     

The corticotropin-releasing hormone test in the postoperative evaluation of patients with cushing's syndrome

After surgical cure of Cushing's syndrome most patients develop transient secondary adrenal insufficiency that lasts for approximately 1 yr. Since ACTH-secreting pituitary adenomas generally respond to ovine CRH (oCRH), we tested the hypothesis that an early postoperative response to oCRH may indicate the presence of residual pituitary tumor and, therefore, predict recurrence. We also assessed the usefulness of oCRH for monitoring the recovery of the hypothalamic-pituitary-adrenal axis and for clarifying the pathophysiology of this condition. Thirty-four patients cured of Cushing's syndrome (29 with Cushing's disease, 3 with adrenal adenomas, and 2 with the ectopic ACTH syndrome) had an evening oCRH test 1-2 weeks after surgery. Nine patients (6 with Cushing's disease, 2 with adrenal adenomas, and 1 with the ectopic ACTH syndrome) participated in a longitudinal evaluation and had repeated oCRH and 1-h ACTH tests at 2-month intervals for a year after surgery. Patients were considered to be cured on the basis of at least 3 subnormal urinary [less than 20 micrograms/24 h (less than 55 nmol/day)] or morning plasma cortisol levels [0600-0900 h; less than 6 micrograms/dL (less than 170 nmol/L)] in the first 2 weeks after surgery. The plasma ACTH and cortisol responses to oCRH in the early postoperative period were subnormal in 23 and normal in 6 patients with Cushing's disease. Three patients developed recurrent Cushing's disease (3, 3, and 23 months after transphenoidal surgery). All 3 were among the 6 who had a normal early postoperative response to oCRH. All of the 23 patients who had a subnormal response to oCRH in the early postoperative period have remained in remission for an average follow-up period of 14 months (6-42 months). Thus, the recurrence rate was significantly greater in patients with normal oCRH tests in the early postoperative period (P less than 0.001, by chi 2 analysis). Surgically cured patients with adrenal adenomas or ectopic ACTH secretion also had subnormal plasma ACTH and cortisol responses to oCRH during the early postoperative period. During longitudinal evaluation for 12 months after surgery, the ACTH and cortisol responses to oCRH increased progressively (regardless of the cause of Cushing's syndrome). Cortisol responses to oCRH correlated significantly with the cortisol responses to exogenous ACTH (r = 0.89; P less than 0.00001). We conclude that most patients with Cushing's syndrome have suppressed responses to oCRH during the early postoperative period.(ABSTRACT TRUNCATED AT 400 WORDS)     

TREATMENT OF CUSHING''S DISEASE IN JUVENILES WITH INTERSTITIAL PITUITARY IRRADIATION

Nine juvenile patients (five boys and four girls aged 10--18 with Cushing's disease were treated with pituitary implantation of 198Au and/or 90Y. No patient had any surgical complication from the procedure. At the latest assessment, 3 months to 17 years after operation, Cushing's disease was in remission in all the patients; the response time following operation was a few days to 3 months. Radiology of the pituitary fossa at time of pituitary implantation was normal in all patients and remains so. The final height in six patients is 149--172 cm (59--67.5 inches) and three patients who continue to grow have increased by 13, 6 and 3 cm since implantation. Only one patient required full pituitary hormone replacement therapy, and he had been previously treated by external irradiation, and one other patient failed to complete puberty. In all the other seven sexual maturation is normal and one has fathered two children. We conclude that pituitary implantation with interstitial irradiation is a satisfactory form of treatment for Cushing's disease in juveniles.     

Adrenocorticotropin levels do not change during early recovery of transsphenoidal surgery for ACTH-secreting pituitary tumors

In patients with ACTH-secreting pituitary tumor the peri-tumoral normal corticotrophs were supposed to be suppressed by cronic hypercortisolemia since frequently they develop transient secondary adrenal insufficiency after pituitary tumor resection and during early postoperative days. We evaluated the ACTH dynamics during transsphenoidal surgery in 16 patients with ACTH-secreting pituitary tumors (6 cured by surgery, 8 not cured Cushing's disease patients and 1 cured by surgery and 1 not cured Nelson's syndrome patients) and tested the hypothesis that in these patients, ACTH secretion from the peri-tumoral normal corticotrophs is inhibited and hence removal of the entire tumor should result in subtle postoperative reduction in plasma ACTH. Blood samples for ACTH determination were obtained from 14 Cushing's disease patients immediately before pituitary gland manipulation and 10, 30, 60, 90, 120, 150 and 300 min after pituitary tumor resection and on postoperative day one. In Nelson's syndrome patients the blood sample was obtained only after tumor removal. All patients received intravenous hydrocortisone during surgery and on the first postoperative day. Patients were considered cured by surgery if they presented adrenal insufficiency after hydrocortisone withdrawal. Mechanical pituitary manipulation induced increase in ACTH level. In all 14 Cushing's disease patients (cured and not cured), mean plasma ACTH levels were significantly greater 10 min after pituitary tumor resection (54.4+/-12.8 pmol/l) than in the premanipulation period (ACTH=26.3+/-5.3 pmol/l) (p=0.005). In Cushing's disease patients, the ACTH levels did not change significantly until 300 min after pituitary tumor resection either in those 6 patients cured by surgery (at 10 min after pituitary tumor resection ACTH was 54.4+/-12.8 pmol/l for all 14 Cushing's disease patients and at 300 min after tumor removal ACTH was 39.0+/-12.6 pmol/l for cured and 41.3+/-15.7 pmol/l for not cured Cushing's disease patients). The ACTH level also persisted high until 300 min after complete pituitary tumor resection in one cured patient with Nelson's syndrome. ACTH level does not change in the early recovery period after ACTH-secreting pituitary tumor, even in those cured patients, and probably peri-tumoral normal corticotrophs are not completely suppressed by cronic hypercortisolemia (and acute glucocorticoid administration) when these patients are under intense stress, like transsphenoidal surgery. Mechanical pituitary manipulation may induce ACTH release in patients with ACTH-secreting pituitary tumors but probably does not interfere in the maintenance of high ACTH-levels during the early postoperative period, since ACTH half-life is only 8-15 min. In patients with ACTH-secreting pituitary tumors, the behavior of the human hypothalamic-pituitary-adrenal system during transsphenoidal surgery does not conform to the specifications of a negative feedback mechanism.     

Results of external pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing's disease.

Fourteen adult patients (10 females and 4 males; age range 20-60 years) with persistent Cushing's disease after transsphenoidal microsurgery were treated with pituitary irradiation. Supervoltage multiportal administration was employed at a total dose of 50 Gy (+/- 0.65 SD). The interval between microsurgery and pituitary irradiation was less than 6 months in 6 patients and more than 6 months in 8. The pituitary-adrenal axis was evaluated postsurgically, before irradiation and every 6 months thereafter. The remaining anterior pituitary function was simultaneously tested. Remission rates at 12 months and 24 months after radiotherapy were 61 and 70%, respectively. Two patients developed TSH deficiency and another gonadotropin deficiency during the follow-up after radiation. We conclude that pituitary irradiation is the treatment of choice for persistent Cushing's disease after unsuccessful surgery because of its high efficiency and low incidence of adverse reactions when compared with other forms of treatment.     

Cyclic Cushing's syndrome

Because glucocorticoids are necessary to sustain life and maintain homeostasis, adrenal disorders, if not detected in a timely fashion, can have serious consequences. Cyclic Cushing's syndrome is a disease characterized by rhythmic fluctuations in glucocorticoid production. In patients with this disorder, both clinical and biochemical spontaneous remissions may occur and therefore the activity of the hypothalamic-pituitary-adrenal axis between the cycles may be undisturbed. The clinical manifestation of cyclic Cushing's syndrome may be complex and varied, differing not only between patients but also in the same patient on a daily to monthly basis. The presence of cyclic Cushing's syndrome should always be considered in patients with a clinical presentation of hypercortisolism coexisting with normal glucocorticoid plasma levels and a paradoxical response to the dexamethasone test. We here present a detailed case report on a patient diagnosed with cyclic Cushing's syndrome. We report diagnostic and treatment strategies used in our patient and their impact on the course and outcome of the disease.