Medical therapy of hypercortisolism (Cushing's syndrome)

1 INTRODUCTION

The hypercortisolism of Cushing's syndrome is primarily treated surgically, regardless of its cause (ie, due to corticotropin [ACTH]-producing pituitary tumor [Cushing's disease], ectopic ACTH secretion by a nonpituitary tumor, or cortisol secretion by an adrenal adenoma or carcinoma). However, when surgery is delayed, contraindicated, or unsuccessful, medical therapy is often required. Adrenal enzyme inhibitors are the most commonly used drugs, but adrenolytic agents, drugs that target a pituitary or ectopic tumor, and glucocorticoid-receptor antagonists are also available.

库欣综合征的高皮质醇症主要通过手术治疗，无论其病因(如，促肾上腺皮质激素[ACTH]产生垂体肿瘤[库欣病]，非垂体肿瘤异位分泌ACTH，或肾上腺腺瘤或癌分泌皮质醇)。然而，当手术延迟，禁忌症，或不成功时，通常需要药物治疗。肾上腺酶抑制剂是最常用的药物，但肾上腺素溶解剂，针对垂体或异位肿瘤的药物，和糖皮质激素受体拮抗剂也可用。

The pharmacologic management of hypercortisolemia in Cushing's syndrome will be reviewed here. An overview of the treatment options for Cushing's syndrome and additional details about drugs that inhibit cortisol synthesis are discussed separately. (See 'Overview of the treatment of Cushing's syndrome' and 'Pharmacology and toxicity of adrenal enzyme inhibitors and adrenolytic agents' and 'Persistent or recurrent Cushing's disease: Surgical adrenalectomy'.)

在这里将回顾库欣综合征高皮质醇血症的药物管理。对库欣综合征的治疗选择的概述和关于抑制皮质醇合成的药物的额外细节分别进行了讨论。

2 INDICATIONS

The main indications for medical therapy of Cushing's syndrome include (see 'Overview of the treatment of Cushing's syndrome'):

库欣综合征的主要治疗指征包括

●Control of hypercortisolism in preparation for surgery – Although the hypercortisolism of Cushing's disease is optimally treated surgically, medical therapy is often required when surgery is delayed. (See 'Overview of the treatment of Cushing's syndrome', section on 'Transsphenoidal surgery'.)

控制高皮质醇血症为手术做准备——虽然库欣病的高皮质醇血症最好通过手术治疗，但如果手术延迟，通常需要药物治疗。

●Management of hypercortisolism if surgery is contraindicated. (See 'Overview of the treatment of Cushing's syndrome', section on 'Medical therapy'.)

如果手术禁忌，治疗高皮质醇症。

●Management of persistent or recurrent hypercortisolism after initial surgery. (See 'Primary therapy of Cushing's disease: Transsphenoidal surgery and pituitary irradiation'.)

初始手术后持续性或复发性皮质醇增多症的处理。

●Patients who have undergone radiation therapy – Control of hypercortisolism while waiting for the effect of pituitary radiation in patients with corticotropin (ACTH)-secreting pituitary tumors (Cushing's disease).

已接受放射治疗的患者——促肾上腺皮质激素(ACTH)分泌垂体肿瘤(库欣病)患者在等待垂体放射治疗的同时控制皮质醇增多症。

●Patients with ectopic ACTH syndrome – Treatment of occult or metastatic ectopic ACTH syndrome.

异位ACTH综合征患者-隐匿性或转移性异位ACTH综合征的治疗。

Our approach is largely consistent with the Endocrine Society Clinical Practice Guideline [1].

我们的方法与内分泌学会临床实践指南[1]基本一致。

3 CHOOSING THERAPIES

Medical treatment of Cushing's syndrome can be divided into two broad categories: medications that decrease cortisol production and those that antagonize the action of cortisol at the glucocorticoid receptor.

库欣综合征的医学治疗可分为两大类:降低皮质醇产生的药物和对抗皮质醇在糖皮质激素受体上的作用的药物。

●Drugs that decrease cortisol production – Drugs that decrease cortisol production include steroidogenesis inhibitors, which act directly on the adrenal gland to inhibit enzymes involved in cortisol synthesis and may also be adrenolytic, and agents that reduce corticotropin (ACTH) secretion by pituitary corticotroph tumors or ectopic tumors, and hence reduce the adrenal stimulation for cortisol production. (See 'Adrenal enzyme inhibitors' below.)

减少皮质醇分泌的药物——减少皮质醇分泌的药物包括类固醇生成抑制剂，它直接作用于肾上腺，抑制参与皮质醇合成的酶，也可能是肾上腺溶解剂，以及垂体促肾上腺皮质激素肿瘤或异位肿瘤减少促肾上腺皮质激素(ACTH)分泌的药物，从而减少肾上腺对皮质醇产生的刺激。

●Glucocorticoid receptor antagonists – An example of a glucocorticoid receptor antagonist is mifepristone. (See 'Glucocorticoid-receptor antagonists' below.)

糖皮质激素受体拮抗剂——糖皮质激素受体拮抗剂的一个例子是米非司酮。

3.1 Issues for all patients

●Patients' goals and preferences – These should be explored together before choosing medical therapy. For example, a young woman's desire for pregnancy in the near future may influence a choice of adrenalectomy over medical treatment. Other potential issues include a preference for oral versus injectable route of administration; daily versus multiple daily doses; impaired memory (ie, possible reduced adherence); a desire to 'get on with life,' which may favor surgery or agents with a faster onset of action; insurance, availability, and affordability.

患者的目标和偏好——在选择药物治疗前应共同探讨这些目标和偏好。例如，年轻女性想要在不久的将来怀孕的愿望可能会影响肾上腺切除术而不是药物治疗的选择。其他潜在的问题包括:更倾向于口服给药而不是注射给药;每日剂量vs每日多次剂量;记忆受损(即，可能减少坚持);一种“继续生活”的愿望，这可能会倾向于手术或更快开始行动的药剂;保险、可用性和负担能力。

●The variability in day-to-day cortisol production – In patients with highly variable cortisol production, fixed dosing regimens may result in adrenal insufficiency alternating with normal or increased cortisol production. Instead, a 'block and replace' strategy is used in which the medication dose is titrated to completely block cortisol secretion, with the addition of a physiologic exogenous glucocorticoid dose to 'replace' cortisol.

皮质醇日常生产的可变性- 对于皮质醇生产高度可变的患者，固定的给药方案可能导致肾上腺机能不全与正常或增加的皮质醇生产交替。取而代之的是，使用“阻断和替代”策略，即滴定药物剂量以完全阻断皮质醇分泌，同时添加生理外源性糖皮质激素剂量以“替代”皮质醇。

Thus, before deciding on a specific medication, 24-hour urine cortisol secretion should be measured to determine the degree of variability of cortisol production. While no studies have identified criteria for 'high' variability, one approach is to look at the percentage or fold changes in at least three pretreatment urinary free cortisol (UFC) values. If the pretreatment values differ by threefold, ideal dosing would achieve values of 20 to 60 mcg/day (within and slightly above the normal range of approximately 5 to 50 mcg/day). However, a result of 20 mcg/day implies threefold results of 0 to 60, risking adrenal insufficiency, and a value of 50 would imply possible results of 17 to 150 mcg/day, risking undertreatment. Thus, a variability criterion of no more than twofold is probably best to use when choosing a fixed-dose regimen.

因此，在决定特定药物治疗前，应测量24小时尿液皮质醇分泌量，以确定皮质醇分泌的可变性程度。虽然没有研究确定“高”可变性的标准，但一种方法是查看经至少三个预处理时尿游离皮质醇(UFC)值的百分比或变化比值。如果预处理后UFC值相差3倍，理想剂量为将达到20至60微克/天(在约5至50微克/天的正常范围内并略高于正常范围)。然而，20微克/天的结果意味着3倍的结果0到60，提示有肾上腺功能不全的风险，而50的值可能意味着17到150微克/天的结果，有治疗不足的风险。因此，在选择固定剂量方案时，不超过两倍的可变性标准可能是最好的。（注解：意指用三倍的剂量比较UFC范围的变化以确定药物敏感性，敏感有肾功能不全的风险，不敏感有治疗不足的风险。）

3.2 Considerations for individual medications 

These issues are discussed below:

●The cause of Cushing's syndrome – Some agents are used only for pituitary Cushing's or ectopic ACTH-producing tumors.

●Likelihood of long-term normalization of signs and symptoms – Some agents are more effective when hypercortisolism is mild. Others may effectively mitigate hypercortisolism but have an adverse side-effect profile that prevents their use or limits long-term use.

●The likelihood of adrenal insufficiency.

●Drug-drug interactions.

3.2对个别药物的考虑

现将这些问题讨论如下:

●库欣综合征的原因——一些药物仅用于垂体库欣或异位ACTH产生肿瘤。

●体征和症状长期恢复正常的可能性——有些药物在轻度高皮质醇症时更有效。其他药物可能有效减轻皮质醇症，但有不良副作用，防止使用或限制长期使用。

●肾上腺功能不全的可能性。

●药物之间的相互作用。

4 INITIAL THERAPY

4.1 Adrenal enzyme inhibitors

Ketoconazole, metyrapone, and mitotane are orally active medications that inhibit one or more steps in cortisol synthesis (figure 1). They are most often used to control corticotropin (ACTH)-dependent cortisol excess [2-6]. These drugs are not available in all countries. The most commonly used agent is ketoconazole in the United States and metyrapone in the United Kingdom. Other drugs that inhibit adrenal enzymes but are either no longer available (aminoglutethimide and trilostane), or rarely used (fluconazole), will not be considered further.

酮康唑、美替拉酮和米托坦是口服活性药物，可抑制皮质醇合成的一个或多个步骤(图1)。它们最常用于控制促肾上腺皮质激素(ACTH)依赖的皮质醇过量[2-6]。并非所有国家都有这些药物。最常用的药物是美国的酮康唑和英国的甲吡酮。不再考虑其他抑制肾上腺酶但已不再使用的药物(氨鲁米特和三氯虫烷)或很少使用的药物(氟康唑)。

figure1 Steroidogenesis in adrenal cortex affected by specific enzyme inhibitors*

Steroidogenesis in the adrenal cortex denoting the specific pathways inhibited by ketoconazole (KTZ), metyrapone (MTR), mitotane, etomidate, and newer steroidogenesis inhibitors.

17-alpha-OH: 17-alpha-hydroxylase; DHEAS: dehydroepiandrosterone sulfate; 3-beta-HSD: 3-beta-hydroxysteroid dehydrogenase; 21-OH: 21-hydroxylase; 11-beta-OH: 11-beta-hydroxylase; LCI699: osilodrostat; 18-OH: 18-hydroxylase.
* Refer to UpToDate table for nomenclature used for steroidogenic enzymes.
¶ Aldosterone synthase.

From: Daniel E, Newell-Price JD. Therapy of endocrine disease: Steroidogenesis enzyme inhibitors in Cushing's syndrome. Eur J Endocrinol 2015; 172:R263. Copyright © 2015 BioScientifica Ltd. All rights reserved.

In addition to inhibiting adrenal enzymes, mitotane is adrenolytic and is used for the treatment of adrenocortical carcinoma (see 'Treatment of adrenocortical carcinoma'). The steroidogenesis inhibitor etomidate is the only agent for intravenous use.

米托坦除了抑制肾上腺酶外，还具有肾上腺溶解作用，用于肾上腺皮质癌的治疗(见“肾上腺皮质癌的治疗”)。类固醇生成抑制剂依托咪酯是静脉注射的唯一药物。

4.1.1 Ketoconazole 酮康唑

Ketoconazole inhibits the first step in cortisol biosynthesis (side-chain cleavage) and, to a lesser extent, the conversion of 11-deoxycortisol to cortisol; it is an even more potent inhibitor of C17-20 desmolase, decreasing androstenedione, testosterone, and estradiol production (figure 1). At therapeutic doses, it also impairs corticotroph adenylate cyclase activation and ACTH secretion in vitro [7]. However, the contribution of this effect to its action in patients with Cushing's disease has not been demonstrated.

酮康唑抑制皮质醇生物合成的第一步(侧链裂解)，并在较小程度上抑制11-脱氧皮质醇转化为皮质醇;它是一种更有效的C17-20去糖化酶抑制剂，能减少雄烯二酮、睾酮和雌二醇的产生(图1)。在治疗剂量下，它还能损害体外[7]中促肾上腺皮质激素腺苷酸环化酶的激活和ACTH的分泌。然而，这种作用对库欣病患者的作用的贡献尚未被证实。

In a series of 200 patients with Cushing's disease, 75 percent achieved either normal free cortisol (UFC) levels (49 percent) or at least a 50 percent decrease, at a median final dose of 600 mg/day. However, 20 percent stopped the treatment due to poor tolerance [8].

在一组200名库欣病患者中，75%达到了正常的游离皮质醇(UFC)水平(49%)或至少降低了50%，最终中位剂量为600毫克/天。然而，20%的患者由于[8]耐受性差而停止了治疗。

Ketoconazole may cause reversible hepatotoxicity [8,9]. In the study described above [8], mild (<5-fold normal values) and major (>5-fold normal values) increases in liver enzymes were observed in 13.5 and 2.5 percent of patients, respectively. In 2013, the US Food and Drug Administration (FDA) issued a warning about the risk of potentially fatal liver toxicity, even in patients without pre-existing hepatic disease [10], which was followed by a temporary withdrawal in European countries. The regulatory warnings were revised to discourage use of ketoconazole for management of fungal infections, and the drug is now widely available [11]. In the United States, it is an off-label use for the treatment of Cushing's syndrome.

酮康唑可引起可逆性肝毒性[8,9]。在上述[8]研究中，在13.5和2.5%的患者中分别观察到轻度(<5倍正常值)和重度(>5倍正常值)的肝酶升高。2013年，美国食品和药物管理局(FDA)发布了一个关于潜在致命肝毒性风险的警告，即使是在没有预先存在肝病[10]的患者中，随后欧洲国家暂停了这一警告。对监管警告进行了修订，以劝阻使用酮康唑治疗真菌感染，目前该药物已被广泛使用。在美国，它是治疗库欣综合征的非适应症药物。

●Liver function tests should be performed before initiation of ketoconazole. The drug is contraindicated in patients with liver disease whose alanine aminotransferase (ALT) values are ≥3 times the upper normal range. Patients with elevated values <3 times the upper normal range often have cortisol-induced nonalcoholic hepatosteatosis that improves with ketoconazole treatment.

在开始使用酮康唑前应进行肝功能检查。肝病患者丙氨酸氨基转移酶(ALT)值≥正常值的3倍，禁用该药。升高值<正常值3倍的患者通常有皮质醇诱导的非酒精性肝骨化，经酮康唑治疗可改善。

●ALT should be monitored weekly for the first month, monthly for three months, and less frequently thereafter.

第一个月每周监测ALT，三个月每月监测ALT，以后减少监测频率。

●If ALT values increase to ≥3 times the upper normal range, we suggest stopping the ketoconazole or reducing it to a previously well-tolerated dose.

如果ALT值升高到高于正常范围≥3倍，我们建议停止酮康唑或将其减少到以前耐受良好的剂量。

Ketoconazole-induced decreases in estradiol and testosterone production may lead to gynecomastia, decreased libido, and impotence in men but usually are not clinically apparent in women because of the oligomenorrhea or amenorrhea associated with Cushing's syndrome [12].

酮康唑诱导的雌二醇和睾酮分泌减少可能导致男性男性乳房发育、性欲下降和阳痿，但通常在女性中临床表现不明显，因为与库欣综合征[12]相关的月经少发或闭经。

Ketoconazole is teratogenic and toxic to animal embryos but has been used successfully and without harm to fetuses from as early as the seventh week of pregnancy [13,14]. However, ketoconazole is not the treatment of choice during pregnancy. (See 'Diagnosis and management of Cushing's syndrome during pregnancy', section on 'Management'.)

酮康唑对动物胚胎有致畸和毒性，但已成功应用，早在妊娠7周时就对胎儿无害[13,14]。然而，酮康唑不是怀孕期间的治疗选择。

Ketoconazole requires an acidic environment for maximal absorption; its bioavailability may be reduced as much as 50 percent if it is given with a proton pump inhibitor [15]. Such agents should be discontinued, if at all possible, if ketoconazole is used.

酮康唑需要酸性环境才能最大吸收; 如果与质子泵抑制剂[15]配合使用，其生物利用度可降低多达50%。如果可能的话，如果使用酮康唑，这些药物应停用。

Ketoconazole is a strong inhibitor of CYP3A4. Coadministration of CYP3A4 substrates should be avoided if possible and may result in increased plasma concentrations of these drugs, with increased or prolonged therapeutic or adverse effects. For example, coadministration of certain ergot derivatives, lovastatin, and alprazolam may result in dangerous elevations of those agents and is contraindicated [16].

酮康唑是CYP3A4的强抑制剂。如果可能，应避免共同给药CYP3A4底物，可能导致这些药物的血浆浓度增加，增加或延长治疗或不良反应。例如，某些麦角衍生物、洛伐他汀和阿普唑仑联合使用可能导致这些药物的危险升高，是禁忌用药。

Ketoconazole can prolong the QT interval; thus concomitant administration of other agents that also prolong the QT interval (such as cisapride, methadone, quinidine) is contraindicated as they may synergize to cause life-threatening ventricular arrhythmia [16].

酮康唑可延长QT间期;因此，同时使用其他也能延长QT间期的药物(如西沙必利、美沙酮、奎宁定)是禁忌的，因为它们可能协同引起危及生命的室性心律失常。

4.1.2 Metyrapone 美替拉酮

We do not suggest metyrapone as the first-line drug for women with Cushing's disease requiring long-term control of hypercortisolism. However, its use is not precluded in women for projected short-term use (for example, for treatment before surgery), or when ketoconazole is not a good alternative.

对于需要长期控制高皮质醇血症的库欣病女性患者，我们不建议首选美泰拉酮作为一线药物。然而，它的使用不排除在妇女的短期计划使用(例如，术前治疗)，或酮康唑不是一个很好的替代。

Metyrapone inhibits CYP11B1, leading to increases in 11-deoxycortisol, the immediate precursor of cortisol. It also inhibits CYP11B2, leading to increases in deoxycorticosterone, the immediate precursor of aldosterone (figure 2), which may cause salt retention and hypertension. As a consequence of decreasing cortisol levels, ACTH secretion from a pituitary tumor may increase, stimulating increases in adrenal androgen production, which can cause hirsutism in women.

美替拉酮抑制CYP11B1，导致11-脱氧皮质醇(皮质醇的直接前体)的增加。它还抑制CYP11B2，导致醛固酮的直接前体脱氧皮质酮的增加(图2)，这可能导致盐潴留和高血压。由于皮质醇水平降低，垂体肿瘤的ACTH分泌可能增加，刺激肾上腺雄激素的产生，从而导致女性多毛症。

figure2 Action of metyrapone

Metyrapone inhibits cortisol production by blocking the conversion of 11-deoxycortisol to cortisol by 11-beta-hydroxylase (CYP11B1).

When given in a dose of approximately 4 g/day, metyrapone decreases cortisol secretion, but usually not to normal, in patients with Cushing's disease [17]. Thus, like the other adrenal enzyme inhibitors, metyrapone is most useful as adjunctive therapy in patients with mild disease or after pituitary irradiation, which prevents a further increase in ACTH secretion [2,18-21]. A dose of 500 to 750 mg three or four times a day is usually required in these patients. Metyrapone has been used in pregnancy with mixed results efficacy [22-24]. (See 'Diagnosis and management of Cushing's syndrome during pregnancy', section on 'Management'.)

在库欣病[17]患者中，当给予约4 g/天的剂量时，美替拉酮可减少皮质醇分泌，但通常不会达到正常水平。因此，与其他肾上腺酶抑制剂一样，美替拉酮在轻度疾病或垂体照射后作为辅助治疗最有用，可防止ACTH分泌进一步增加[2,18-21]。这些病人通常需要每天三到四次服用500到750毫克的剂量。美替拉酮已用于妊娠，疗效不一[22-24]。

In the largest retrospective, multicenter series, 195 patients with Cushing's syndrome (all causes) were treated with metyrapone (as monotherapy in 84 percent) [25]. Complete normalization of cortisol secretion was achieved in approximately 50 percent of patients treated both short and long term. Among 38 patients treated long term (mean 18 months), 77 percent achieved complete normalization of cortisol secretion. The drug was generally well tolerated: gastrointestinal upset (23 percent) and hypoadrenalism (7 percent) were the most frequent side effects; hypokalemia, hypertension, and hirsutism were very seldom found.

在最大的多中心回顾性研究中，195例库欣综合征(所有病因)患者接受了美替拉酮[25]治疗(84%为单药治疗)。在接受短期和长期治疗的患者中，大约50%的皮质醇分泌完全正常化。在38例长期治疗的患者中(平均18个月)，77%的患者达到了皮质醇分泌完全正常化。该药的耐受性普遍良好:胃肠道不适(23%)和肾上腺机能减退(7%)是最常见的副作用;低钾血症、高血压和多毛症极少见。

Metyrapone is currently available in North America through its distributor HRA Pharma (Paris, France) via its specialty pharmacy Direct Success Inc with order forms available on the web (www.metopirone.us) or by phone at 1-855-674-7663. Like ketoconazole, its use for treatment of Cushing's syndrome is an off-label use.

4.1.3 Osilodrostat  奥西罗司他？

Osilodrostat is an oral agent that has been approved for adults with Cushing's disease who are not candidates for pituitary surgery or who have undergone transsphenoidal surgery but have persistent disease [26-28]. Like metyrapone, it blocks the 11-beta-hydroxylase enzymes (CYP11B1 and CYP11B2), thereby reducing the synthesis of aldosterone and cortisol [26]. Osilodrostat's safety and effectiveness for treating adults with Cushing's disease was evaluated in a six-month, single-arm, open-label study of 137 adult patients with Cushing's disease, who were either not surgical candidates or who had undergone transsphenoidal surgery but were not cured. The starting dose for all was 2 mg twice daily that could be increased by 1 to 2 mg every two weeks up to 30 mg twice/day. At the end of 24 weeks, approximately one-half of patients had 24-hour UFC levels less than or equal to the upper limit of normal (ULN) [29].

Osilodrostat是一种口服药物，已被批准用于库欣病成人患者，这些患者不适合进行垂体手术或接受过蝶窦手术但有持续性疾病[26-28]。像甲吡酮一样，它阻断11- β -羟化酶(CYP11B1和CYP11B2)，从而减少醛固酮和皮质醇[26]的合成。在一项为期6个月的单臂开放标签研究中，评估了Osilodrostat治疗成人库欣病的安全性和有效性，该研究对137例成年库欣病患者进行了研究，这些患者要么没有接受手术，要么接受了经蝶窦手术但未治愈。所有药物的起始剂量均为每天两次2毫克，可每两周增加1至2毫克，直至每天两次30毫克。在24周结束时，大约有一半的患者24小时UFC水平小于或等于正常(ULN)[29]的上限。

In this same trial, subjects who achieved a 24-hour UFC less than or equal to ULN at week 24, without up-titration after week 12, entered into an 8-week randomized trial of continued osilodrostat or placebo [30]. Of the 137 patients initially enrolled, 72 were eligible for the randomized trial. More patients maintained a complete response with osilodrostat than placebo (86 versus 29 percent, respectively).

在同一试验中，在第24周时24小时UFC小于或等于ULN，且在第12周后未加滴定的受试者，进入了一项8周的持续奥西罗司他或安慰剂[30]的随机试验。在最初纳入的137例患者中，有72例符合随机试验的条件。与安慰剂相比，使用奥西罗司他的患者保持完全缓解的比例更高(分别为86%和29%)。

Side effects of the drug include hypocortisolism, prolongation of the QT interval, nausea, headache, and adrenal insufficiency [27,30,31]. There are limited data on a faster dose escalation strategy or use of the agent in patients without Cushing's disease. In one report of three patients with ectopic ACTH secretion, the dose was increased by 1 mg every two to five days, based on morning plasma cortisol levels [32].

该药物的副作用包括低皮质醇血症、QT间期延长、恶心、头痛和肾上腺机能不全[27,30,31]。在没有库欣病的患者中，快速增加剂量策略或使用该药物的数据有限。在一份三例异位ACTH分泌患者的报告中，根据早晨血浆皮质醇水平[32]，剂量每2到5天增加1 mg。

4.1.4 Mitotane 米托坦

Mitotane is an adrenolytic drug that acts on adrenocortical cell mitochondria to inhibit CYP11B1 (11-beta-hydroxylase) and cholesterol side-chain cleavage (CYP11A1) enzymes. A metabolite binds to important macromolecules in the mitochondria, causing mitochondrial destruction and necrosis of adrenocortical cells [33]. Because of its adrenolytic action, it is used primarily for the treatment of adrenal carcinoma, which will not be considered further here. (See 'Treatment of adrenocortical carcinoma', section on 'Adjuvant mitotane'.)

米托坦是一种肾上腺素溶解药物，作用于肾上腺皮质细胞线粒体，抑制CYP11B1 (11- β -羟化酶)和胆固醇侧链切割(CYP11A1)酶。一种代谢物与线粒体中的重要大分子结合，导致线粒体破坏和肾上腺皮质细胞[33]坏死。由于它的肾上腺溶解作用，它主要用于肾上腺癌的治疗，这在这里不再进一步讨论。

Mitotane also can be used to achieve medical adrenalectomy with or without pituitary irradiation in patients with Cushing's disease or as an adjunctive medication in patients with ectopic ACTH secretion [34-36]. Mitotane treatment of Cushing's syndrome not caused by adrenocortical cancer should be started with 0.5 g given at bedtime, adding single 0.5 g doses at a mealtime every week or so, as the patient's tolerance permits, to reach a maximal dose of 2 to 3 g/day, one-half of which is taken at bedtime to reduce nausea. Thereafter, the concentrations are maintained by doses of 1 to 2 g daily. At these doses, mitotane tends to spare the zona glomerulosa [37] so that mineralocorticoid replacement is not needed.

米托坦也可用于库欣病患者行内科肾上腺切除术(无论垂体照射与否)，或作为异位ACTH分泌患者的辅助药物[34-36]。米托坦治疗库兴氏综合征(不包括肾上腺皮质癌引起的）开始剂量于睡前0.5 g, 每一个星期左右增加单次剂量0.5克于进餐时间，在病人耐受达到最大剂量的2 - 3克/天, 可采取睡前服用一半以减少恶心。此后，每天服用1至2克维持浓度。在这些剂量下，米托坦倾向于使肾小球带免于[37]，因此不需要矿物皮质激素替代。

The major side effects are nausea, vomiting, and anorexia. Additional side effects that occur with the higher doses used for adrenal carcinoma are discussed separately. (See 'Treatment of adrenocortical carcinoma', section on 'Adjuvant mitotane'.)

主要的副作用是恶心、呕吐和厌食。额外的副作用发生与高剂量用于肾上腺癌分别讨论。

When given as adjunctive therapy after radiotherapy for Cushing's disease, mitotane is stopped when cortisol levels normalize, on average after six to nine months. A sustained cure rate was reported in approximately 60 percent of cases at 5 to 15 years [34]. Similar findings were reported in a study of 46 patients treated with higher doses of mitotane but no pituitary irradiation [35]. Four of 92 patients developed Nelson syndrome.

作为库欣病放疗后的辅助治疗，平均在6至9个月后，当皮质醇水平恢复正常时，米托坦就会停止。据报道，在5到15年[34]时，大约60%的病例有持续治愈率。在一项对46例患者进行高剂量米托坦但无垂体照射[35]的研究中也有类似的发现。92名患者中有4人患上了尼尔森综合症。

Mitotane is taken up by adipose tissues and persists in plasma long after the drug is discontinued [38]. Mitotane is teratogenic and should not be given to pregnant women; women anticipating pregnancy should have levels measured after its discontinuation to ensure that it is safe to proceed [39].

米托坦被脂肪组织吸收，并在[38]停药后长期存在于血浆中。米托坦是致畸剂，不应给孕妇服用; 孕妇在停用[39]后应测量[39]水平，以确保进行[39]是安全的。

4.2 Dose adjustments and monitoring — Unless mitotane is given in adrenolytic doses, these medications do not permanently cure the hypercortisolism, leading to recurrence when the drug is discontinued. As a result, they must be continued indefinitely until bilateral adrenalectomy is performed, or a tumor is found and excised or pituitary radiotherapy is effective.

剂量调整和监测——除非米托坦以肾上腺素溶解剂的剂量给药，否则这些药物不能永久治愈高皮质醇症，导致停药后复发。因此，它们必须无限期地持续，直到进行双侧肾上腺切除术，或发现肿瘤并切除，或垂体放射治疗有效。

●Ketoconazole/metyrapone/osilodrostat – Doses of ketoconazole and metyrapone can be increased every three to seven days based on serum cortisol and/or urine cortisol excretion. In clinical trials, the osilodrostat dose was adjusted every two weeks; this dose adjustment period is recommended in the FDA label. At the outset of treatment with these steroidogenesis inhibitors, we recommend measurement of a morning serum cortisol level on the day that urine is returned for cortisol measurement. This allows the two to be correlated, allowing later use of the morning cortisol only, as most patients find a blood draw to be more convenient than urine collection.

●酮康唑/美替拉酮/奥西罗司他 -酮康唑和美替拉酮的剂量每3 - 7天可根据血清皮质醇和/或尿液皮质醇排泄增加一次。在临床试验中，奥西罗司他每两周调整一次剂量; 这个剂量调整期在FDA标签中是推荐的。在使用这些类固醇生成抑制剂治疗的开始，我们建议在返回尿液进行皮质醇测量的当天早上测量血清皮质醇水平。这使得两者相互关联，只允许晚些时候使用早上的皮质醇，因为大多数病人发现抽血比收集尿液更方便。

●For patients with relatively invariant cortisol production, a fixed dose schedule can be used with the goal of 'normalization' of cortisol. A serum cortisol target of 7 to 12 mcg/dL (193 to 331 nmol/L) can be used while awaiting the urine result, with a goal urine value in the middle to slightly above the upper limit of the reference range. While this approach minimizes the chance of adrenal insufficiency, patients nevertheless should receive education about adrenal insufficiency signs and symptoms and how to administer emergency doses of glucocorticoid. (See 'Treatment of adrenal insufficiency in adults'.)

对于皮质醇产生相对不变的患者，可以使用固定的剂量计划，以实现皮质醇的“正常化”。在等待尿液结果时，血清皮质醇指标为7 - 12 mcg/dL (193 - 331 nmol/L)，目标尿值位于中间，略高于参考值范围的上限。虽然这种方法最大限度地减少了肾上腺机能不全的机会，但患者仍应接受有关肾上腺机能不全的体征和症状的教育，以及如何给药紧急剂量的糖皮质激素。

●For patients requiring a 'block and replace' strategy, the dose of drug(s) is increased at intervals until serum or urine cortisol is in the normal range, at which time a glucocorticoid is added. The dose is increased further until serum or urine cortisol values are very low or undetectable. (See 'Replacement glucocorticoid therapy' below.)

对于需要“阻断并替代”策略的患者，药物剂量会每隔一段时间增加一次，直到血清或尿液皮质醇处于正常范围，这时就会添加糖皮质激素。剂量进一步增加，直到血清或尿液皮质醇值很低或检测不到。

●Once the dose appears to be optimal, monitoring may occur less often, perhaps monthly or less frequently.

一旦剂量达到最佳，监测次数可能会减少，可能是每月一次或更少一次。

●Metyrapone administration increases 11-deoxycortisol, which may cross-react with the antibodies in some cortisol immunoassays, while tandem mass spectrometry results are not affected [40]. If urine or serum cortisol measurement by tandem mass spectrometry is not available, a cortisol immunoassay that does not cross-react with 11-deoxycortisol should be used.

美替拉酮给药增加11-脱氧皮质醇，在某些皮质醇免疫检测中可能与抗体发生交叉反应，而串联质谱结果不影响[40]。如果不能用串联质谱法测定尿液或血清皮质醇，则应使用与11-脱氧皮质醇不发生交叉反应的皮质醇免疫测定法。

●Mitotane – Doses of mitotane are increased more slowly, due to its long half-life. Urinary cortisol excretion is the optimal measure of the efficacy of mitotane therapy. Mitotane increases cortisol-binding globulin (CBG) levels, so that serum cortisol levels increase and do not reliably reflect biologically active free levels [41]. If serum cortisol levels are used to monitor treatment, they should be correlated with urinary cortisol excretion, at least initially and after dose changes.

米托烷-由于米托烷的半衰期较长，剂量增加的速度较慢。尿皮质醇排泄是米托坦治疗效果的最佳衡量标准。米托坦增加皮质醇结合球蛋白(CBG)水平，因此血清皮质醇水平升高，不能可靠地反映生物活性游离水平[41]。如果用血清皮质醇水平来监测治疗，它们应该与尿皮质醇排泄相关，至少在初始和剂量变化后是这样。

4.3 Replacement glucocorticoid therapy 糖皮质激素替代治疗

In a block and replace strategy, patients must receive replacement glucocorticoid therapy when the serum or urine cortisol is in the normal range.

在阻断和替代策略中，当血清或尿液皮质醇处于正常范围时，患者必须接受替代糖皮质激素治疗。

●When ketoconazole, osilodrostat, and/or metyrapone are used to decrease cortisol levels, any glucocorticoid replacement can be used in the usual way (see 'Treatment of adrenal insufficiency in adults'). If hydrocortisone is used, urine collections to assess efficacy must be done after switching to dexamethasone, which does not cross-react in cortisol assays. Alternatively, a pre-hydrocortisone serum cortisol level can be used to monitor therapeutic effectiveness, with a goal of very low or undetectable level of urine or serum cortisol.

当酮康唑、奥西罗司他和/或美替拉酮被用来降低皮质醇水平时，任何糖皮质激素替代品都可以以通常的方式使用(见“成人肾上腺功能不全的治疗”)。如果使用氢化可的松，在改用地塞米松后必须收集尿液以评估疗效，地塞米松在皮质醇测定中没有交叉反应。另外，氢化可的松前血清皮质醇水平可以用来监测治疗效果，目标是尿液或血清皮质醇水平非常低或检测不到。

●When mitotane is used, one cannot predict when a patient will become hypocortisolemic. As a result, replacement glucocorticoid, usually 5 mg of prednisone or 0.5 mg of dexamethasone each day, should be started when cortisol in urine or saliva begin to decrease. Mitotane increases the metabolism of dexamethasone [42], fludrocortisone, and cortisol and induces an increase in CBG levels [5]. Thus, replacement dose hydrocortisone usually requires a two- to threefold increase in the usual dose after long-term therapy with mitotane. (See 'Treatment of adrenocortical carcinoma', section on 'Adjuvant mitotane'.)

当使用米托坦时，我们无法预测患者何时会出现低糖皮质激素血症。因此，当尿液或唾液中的皮质醇开始减少时，就应该开始替代糖皮质激素，通常是每天5毫克强的松或0.5毫克地塞米松。米托坦增加地塞米松[42]、氟代可的松和皮质醇的代谢，并诱导CBG水平[5]的升高。因此，在米托坦长期治疗后，氢化可的松的替代剂量通常需要增加两到三倍。(见“肾上腺皮质癌的治疗”，“佐剂米托坦”一节。)

If dexamethasone is used for replacement therapy during mitotane administration, it may be necessary to increase its dose (and that of fludrocortisone, if it is required) to three to seven times the usual dose; in these cases, amelioration of symptoms of hypocortisolism or normalization of UFC values must be used to guide glucocorticoid replacement, while symptoms and signs of volume depletion or excess (postural hypotension, systemic hypertension, or edema), serum electrolytes, and plasma renin activity are used to guide mineralocorticoid replacement. (See 'Treatment of adrenal insufficiency in adults'.)

如果在给米托坦期间使用地塞米松替代治疗，可能需要增加其剂量(以及氟可的松，如果需要)至通常剂量的3至7倍;在这些情况下,改进的症症状的低皮质醇症或正常化终极格斗冠军赛值必须该病可以用于指导糖皮质激素替代,而体积损耗或者过量的症状与体征(体位低血压、系统性高血压、水肿)、血清电解质、血浆肾素活性是用于指导盐皮质激素替代。

Because mitotane levels may remain measurable for months after its discontinuation due to release from adipose tissue, cortisol levels may remain suppressed so that replacement glucocorticoid may have to be tapered over a period of several weeks to months.

由于米托坦的水平可能在停止使用后的几个月仍可测量，由于脂肪组织的释放，皮质醇水平可能会继续受到抑制，因此替代糖皮质激素可能需要在几周到几个月的时间内逐渐减少。

4.4 Combination therapy

Combinations of these drugs often have additive or synergistic therapeutic effects at lower individual doses, thereby minimizing side effects.

这些药物的组合通常在较低的个人剂量下具有附加或协同治疗效果，从而最大限度地减少副作用。

●If ketoconazole does not control cortisol secretion, it should be maintained at a total dose of 1200 mg/day and metyrapone and/or mitotane should be added.

如果酮康唑不能控制皮质醇分泌，总剂量应维持在1200mg /天，并应添加美替拉酮和/或米托坦。

●We suggest adding metyrapone at a dose of 250 mg two or three times a day and increasing rapidly, to a maximum dose of approximately 4.5 g/day [15]. Most patients show near-maximal responses at a daily dose of 2 g (see 'Metyrapone' above). Particularly in patients with severe hypercortisolism, it is important to control cortisol synthesis quickly. In these patients, the doses should be increased every two or three days if laboratory results are available.

我们建议以250毫克的剂量，每天2 - 3次，并迅速增加，最大剂量约为4.5克/天[15]。大多数患者在每日2 g的剂量下表现出接近最大的反应(见上面的“甲替拉酮”)。特别是在严重的高皮质醇症患者中，迅速控制皮质醇合成非常重要。在这些病人中，如果有化验结果，剂量应每两三天增加一次。

●An alternative approach is to begin treatment with metyrapone and add ketoconazole if cortisol is not adequately controlled.

另一种方法是在皮质醇控制不充分的情况下，先用美替拉酮治疗，再加酮康唑。

●In one study of 11 cases of severe hypercortisolism in whom adrenalectomy was not feasible, triple drug therapy with mitotane, metyrapone, and ketoconazole normalized UFC [43].

在一项研究中，11例肾上腺切除术不可行的严重高皮质醇症患者，采用米托坦、美替拉酮和酮康唑三联药物治疗使UFC[43]正常化。

4.5 Intravenous etomidate 静脉注射依托咪酯

Etomidate is a substituted imidazole anesthetic drug that blocks CYP11B1 synthesis of cortisol and is the only available agent for hospitalized patients unable to take medication by mouth (figure 3). Etomidate is infused intravenously, initially with a low, nonhypnotic dose of 0.04 to 0.05 mg/kg per hour (approximately 2.5 to 3 mg/hour), with dose titration based upon serum cortisol (up to 0.1 to 0.3 mg/kg/hour). This approach has been effective in approximately 30 adults and children who were acutely ill [44]. It lowers serum cortisol to normal (ie, 10 mcg/dL [28 nmol/L]) within approximately 10 hours [5]. Monitoring in an intensive care unit is suggested when using etomidate. Intravenous hydrocortisone is added if complete block rather than cortisol normalization is the goal. Sedation, a theoretical side effect of this drug, was not observed in the few patients studied to date.

依托咪酯是一种取代咪唑麻醉药物，可阻断皮质醇CYP11B1的合成皮质醇并且是唯一可用于不能口服药物的住院病人的药物(图3)。依托咪酯注入静脉注射,最初与低,nonhypnotic剂量的每小时0.04至0.05毫克/公斤(大约2.5到3毫克/小时),以血清皮质醇为基础的剂量滴定(可达0.1至0.3 mg/kg/小时)。这种方法在大约30名急性[44]的成人和儿童中有效。它能在大约10小时[5]内将血清皮质醇降低到正常水平(即10 mcg/dL [28 nmol/L])。使用依托咪酯时，建议在重症监护病房进行监护。如果目标是完全阻断而不是皮质醇正常化，则需要静脉注射氢化可的松。镇静，一种理论上的药物副作用，在少数病人的研究中没有观察到。

figure 3 Normal adrenal steroidogenesis

(A) Zona glomerulosa (ZG): Controlled primarily by the renin-angiotensin system through angiotensin II as well as potassium ion and ACTH (acutely). Renin secretion is stimulated by hyponatremia, hypovolemia, and hypotension. The ultimate increase in angiotensin II causes vasoconstriction and stimulates aldosterone, thereby increasing renal sodium reabsorption resulting in an expansion of plasma volume.
(B) Zona fasciculata (ZF): Cortisol is the major product because CYP17A1 (17-hydroxylase activity*) predominates. The square brackets ([ ]) indicate that corticosterone synthesized from progesterone by CYP21A2 and then CYP11B1 is usually a minor pathway (except in CYP17A1 [17-hydroxylase*] deficiency).
(C) Zona reticularis (ZR): The question mark (?) indicates that there are other as yet defined factors involved in the control of steroidogenesis in the ZR. The square brackets ([ ]) indicate that HSD3B2 production of androstenedione is a minor pathway in the ZR. However, not shown is that DHEA from the ZR is converted to androstenedione (and then testosterone) in peripheral tissues.

ACTH: corticotropin.
* CYP17A1 has high 17-hydroxylase activity in the zona fasciculata, but has minimal 17,20-lyase activity because of low expression of a cofactor (cytochrome b5) necessary for full 17,20-lyase activity. Therefore, the ZF is not a source of significant adrenal androgen precursors as in the ZR (C).
¶ In the ZR, CYP17A1 catalyzes 17-hydroxylase and 17,20-lyase activity because of the presence of a cofactor (cytochrome b5).

Courtesy of Hershel Raff, PhD.

5 OTHER AGENTS

5.1 Drugs that target a pituitary tumor — Only the somatostatin analogue, pasireotide, and the dopamine agonist, cabergoline, have shown benefit; other agents that are not effective include bromocriptine, cyproheptadine, and valproate.

5.1.1 Cabergoline 卡麦角林 — Cabergoline is useful when Cushing's disease is associated with urinary free cortisol (UFC) values up to twice normal. In two studies, chronic cabergoline therapy (1 mg once weekly to 1 mg orally every day) decreased 24-hour UFC to ≤125 percent of normal in 12 of 42 patients with Cushing's disease [45,46]. Normalization of UFC was achieved in 30 percent of patients with up to five years of follow-up [46]. A meta-analysis found that patients with milder hypercortisolism were more likely to respond [47]. Gastrointestinal side effects, particularly nausea (14 percent) and dizziness were most common; severe adverse effects included adrenal insufficiency and hypotension. The agent has been used in a small number of pregnant women with good outcomes [48].

5.1.2 Pasireotide 帕瑞肽 — The somatostatin analog pasireotide binds to somatostatin receptors and blocks the release of corticotropin (ACTH) from the corticotrophs via its high affinity for somatostatin receptor subtype 5 [49]. Pasireotide injection has been approved in the United States, Europe, Canada, and parts of Asia and South America and is recommended for the treatment of patients with Cushing's disease for whom surgery has been unsuccessful or who are not surgical candidates [1,50]. It is available as a short-acting subcutaneous preparation for twice-daily use and as a once-monthly intramuscular (IM) injection. In a study of 162 patients with Cushing's disease receiving subcutaneous pasireotide (0.6 or 0.9 mg twice daily for six months), 24-hour UFC decreased by a mean of 48 percent in the whole group and normalized it in 21 of 80 (26 percent) and 12 of 82 (15 percent) of those in the 0.9 or 0.6 mg group, respectively [51]. Patients who achieved UFC control also experienced other clinical improvements, including a decrease in total and low-density lipoprotein cholesterol [52]. Reductions in blood pressure and body mass index occurred even without normalization of UFC. Hyperglycemia was common, occurring in 118 of 162 patients (73 percent); 74 of 162 patients (63 percent) required initiation of a glucose-lowering medication. Pasireotide-associated hyperglycemia is related to decreases in insulin secretion and incretin hormone responses (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), but not to changes in hepatic/peripheral insulin sensitivity [53]. Other side effects were similar to other somatostatin analogs (gastrointestinal symptoms and gallstones). (See 'Treatment of acromegaly'.)

The recommended initial dose of the short-acting formulation is 0.6 mg subcutaneously twice daily, which may be increased to 0.9 mg twice daily if UFC does not normalize after one to two months of therapy. If there is no clinical response to 0.9 mg, treatment should either be stopped or combined therapy should be considered. A sustained response for up to five years has been reported in three individuals [54,55]; two had initially developed glucose intolerance with pasireotide, but with clinical and biochemical reversal of their hypercortisolism, they were eventually able to discontinue all diabetes pharmacotherapy [55].

A long-term study of 53 patients showed a tumor volume reduction of at least 20 percent at 6 and 12 months that was more common in those taking the 0.9 mg dose than the 0.6 mg dose (75 and 89 percent versus 44 and 50 percent) [56].

In a trial of 150 patients receiving either 10 or 30 mg once-monthly IM pasireotide for 12 months, approximately 40 percent in each group reached the primary endpoint (UFC concentration less than or equal to upper limit of normal by seven months) [57]. Adverse events include hyperglycemia (47 to 49 percent), diarrhea (35 to 43 percent), gallstones (20 to 45 percent), and type 2 diabetes (19 to 24 percent). In an open-label extension study that enrolled 81 of the 150 patients, the safety profile was similar to that reported in the first 12 months [58]. The recommended starting dose for pasireotide is 10 mg.

The monthly preparation may be useful for patients who have difficulty remembering to take medications, but is not a first-line choice for patients with diabetes.

The pasireotide warning and precaution for hyperglycemia and diabetes has been updated to include ketoacidosis [59].

5.2 Drugs that target an ectopic ACTH-secreting tumor

Chemotherapy or immunotherapy may reduce corticotropin (ACTH) and cortisol levels in patients with ectopic ACTH secretion [60-62]. A few patients have been successfully treated with octreotide and/or cabergoline [63-65]. However, these are case reports or small series, and the overall efficacy of these approaches is not known.

5.3 Combination therapy

In a report of 17 patients with Cushing's disease, the somatostatin analog pasireotide, followed by cabergoline, and, if necessary, ketoconazole, achieved normalization in UFC in five (29 percent for pasireotide alone), four (53 percent for pasireotide and cabergoline), and six patients (88 percent for three drugs), respectively [66].

In another report, for patients in whom cabergoline therapy (3 mg/week) provided a suboptimal response, addition of ketoconazole (200 to 400 mg daily) achieved a normal UFC in six of nine patients [45].

In another study, cabergoline (n = 6, dose up to 3 mg weekly) or ketoconazole (n = 8, daily dose of 200 to 600 mg) was the first agent for four to six months [67]. UFC remained abnormal with the initial treatment but normalized in 13 patients on combination therapy.

The combination of mitotane (3 to 5 g/24 hours), metyrapone (3 to 4.5 g/24 hours), and ketoconazole (400 to 1200 mg/24 hours) was able to rapidly correct severe hypercortisolism in a series of 11 cases of Cushing's syndrome in acute care situations [43].

5.4 Glucocorticoid-receptor antagonists

Mifepristone (RU-486) is an anti-progestational drug that is best known as an abortifacient. At much higher doses, it acts as a glucocorticoid receptor antagonist. Currently, mifepristone is the only available glucocorticoid antagonist, although other agents are in clinical trials.

Mifepristone is approved in the United States as a once-daily oral medication to control hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome and type 2 diabetes or glucose intolerance who have failed surgery or are not candidates for surgery [68]. Because patients were not categorized as clinically normal during treatment, the role of mifepristone apart from treatment of hyperglycemia is not clear [69].

Mifepristone may be a reasonable short-term intervention for patients with Cushing's syndrome who have an acute crisis, such as cortisol-induced psychosis, as symptoms improve rapidly in response to the glucocorticoid receptor blockade [70,71].

Mifepristone also blocks the action of exogenous glucocorticoids, making it difficult to treat symptoms of adrenal insufficiency. Should symptoms of adrenal insufficiency occur, we suggest giving dexamethasone 4 mg to overcome the blockade.

Because mifepristone blocks cortisol action, the levels of ACTH and cortisol increase in patients with Cushing's disease [72] and are variable in patients with ectopic ACTH secretion [73], so that hormonal measurement cannot be used to judge either therapeutic efficacy or adrenal insufficiency. Instead, the goal is normalization of clinical and biochemical manifestations of hypercortisolism in each individual. For example, if hypertension, weight gain, and diabetes are signs/symptoms for a specific patient, monitoring should ensure that these improve and then resolve. It may be helpful to develop a list of each patient's signs and symptoms of Cushing's syndrome and then monitor these regularly, increasing the dose of the medication if they do not improve.

SUMMARY AND RECOMMENDATIONS

●The hypercortisolism in Cushing's syndrome is primarily treated surgically, regardless of its cause. However, when surgery is delayed, contraindicated, or unsuccessful, medical therapy is often required. (See 'Indications' above.)

库欣综合征的高皮质醇症主要是手术治疗，无论其原因。然而，当手术延迟、禁忌或不成功时，通常需要药物治疗。

●The main indications for pharmacologic control of hypercortisolism include: in preparation for surgery, persistence or recurrence of hypercortisolism after surgery, while waiting for the effect of pituitary radiation, occult ectopic corticotropin (ACTH) syndrome, severe or malignancy-related hypercortisolism, and when surgery is contraindicated. (See 'Indications' above.)

hypercortisolism的药物控制的主要指标包括:  在术前准备, 术后高皮质醇症持续或复发, 在等等待脑垂体辐射的效果 ,隐匿型异位促肾上腺皮质激素(ACTH)综合征, 严重或恶性相关的高皮质醇症,当手术禁忌。

●Among patients with hypercortisolism in whom medical therapy is indicated, we suggest ketoconazole as initial therapy (Grade 2C). Liver function tests must be carefully monitored because of rare occurrences of hepatotoxicity (see 'Ketoconazole' above). If ketoconazole does not control cortisol secretion, we suggest adding metyrapone (Grade 2C). (See 'Initial therapy' above.)

在需要药物治疗的高皮质醇症患者中，我们建议酮康唑作为初始治疗(2C级)。由于肝毒性的罕见发生，必须仔细监测肝功能检查(见上文“酮康唑”)。如果酮康唑不能控制皮质醇分泌，我们建议添加美替拉酮。

●An alternative approach is to start with metyrapone and add ketoconazole if cortisol secretion is not controlled. (See 'Issues for all patients' above.)

另一种方法是在皮质醇分泌不受控制的情况下，先用美替拉酮，再加入酮康唑。

●Mitotane is an adrenocorticolytic drug that is used primarily for the treatment of adrenal carcinoma. (See 'Mitotane' above.)

米托坦是一种肾上腺皮质溶解药物，主要用于肾上腺癌的治疗。

●Mitotane also can be used to as adjunctive therapy during or after pituitary irradiation in patients with Cushing's disease. The usual duration of mitotane therapy in patients with Cushing's disease is six to nine months. (See 'Mitotane' above.)

米托坦也可用于库欣病患者垂体辐照期间或之后的辅助治疗。库欣病患者米托坦治疗的通常持续时间为6至9个月。

●Mitotane has significant side effects. However, important advantages over surgical adrenalectomy include a possible decreased risk of developing Nelson syndrome and the possibility of not requiring mineralocorticoid replacement. (See 'Mitotane' above.)

米托坦有明显的副作用。然而，与肾上腺手术相比，肾上腺切除术的重要优势包括可能降低纳尔逊综合征的风险，以及不需要矿物皮质激素替代的可能性。

●Drugs directed at reducing ACTH levels in Cushing's disease include the dopamine agonist, cabergoline (off-label use), and the parenteral somatostatin analog pasireotide (approved for therapy of Cushing's disease). (See 'Cabergoline' above and 'Pasireotide' above.)

用于降低库欣病ACTH水平的药物包括多巴胺激动剂、卡麦角林(适应症外使用)和肠外生长抑素类似物pasireotide(批准用于库欣病治疗)。

●Mifepristone, a glucocorticoid-receptor antagonist, is approved in the United States for treatment of hyperglycemia in Cushing's syndrome patients who cannot undergo surgery. (See 'Other agents' above.)

米非司酮是一种糖皮质激素受体拮抗剂，在美国被批准用于不能接受手术的库欣综合征患者的高血糖治疗。

DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

披露-在本专题中表达的观点是作者的观点，并不反映美国政府或其组成部分的官方观点或政策。

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