Newman C B
Department of Clinical Medicine, New York University School of Medicine, New York, USA.
Endocrinol Metab Clin North Am. 1999 Mar;28(1):171-90. doi: 10.1016/s0889-8529(05)70062-1.
Both somatostatin analogues, which bind to the somatostatin receptor subtypes 2 and 5, and dopamine agonists, which are specific for the D2 receptor, have been used to treat acromegaly. Each of these classes of drugs contains several compounds that vary in duration of action, efficacy, and side effect profile. Although somatostatin analogues reduce GH levels and alleviate symptoms in most patients and restore IGF-1 levels to normal in 60% to 65% of patients, tumor shrinkage is limited to 40% of patients. evidence in the literature supports the use of these medications as secondary therapy in patients with acromegaly who have had surgery and who continue to have elevated GH levels (above 2 ng/mL during an oral glucose tolerance test) with or without IGF-1 concentrations that are above the upper limit of normal for age. In addition, medical therapy indicated in patients who refuse surgery and in patients who are poor surgical candidates. The controversial question is whether medical therapy should be an option for primary treatment of the acromegalic patient. Currently, ther are no data from prospective randomized trials comparing the effects of surgery versus somatostatin analogues as first-line therapy for for newly diagnosed acromegalic patients. Limited data from nonrandomized studies demonstrate that somatostatin analogues are effective long-term in suppressing GH and reducing IGF-1 into the normal range in approximately two-thirds of patients who have never undergone previous treatment. It is still the consensus that patients with GH-secreting microadenomas should undergo surgical resection, because the likelihood of complete cure by an experience neurosurgeon is high, at least 70% or greater. Successful surgical treatment has the advantage of completely removing the tumor in contrast to medical therapy, which rarely produces shrinkage greater than 50% despite the fact that IGF-1 and GH levels may be normal. In patients with macroadenomas of a size and location that suggest that the chance of complete resection is 40% or less, primary treatment with a somatostatin analogue should be considered as one option in the initial management of the patient. Another option in such an individual would be surgical debulking followed by medical therapy, because it is theoretically possible that biochemical cure with medical therapy after surgical debulking might be achieved with lower doses. The cost-effectiveness of these approaches has not yet been determined. Once the decision has been made to begin medical therapy, a choice must be made between dopamine agonists and somatostatin analogues. Most evidence suggests that somatostatin analogues are more effective than dopamine agonists and therefore would be the therapy of choice. In select patients, dopamine agonists, particularly the long-acting agonist cabergoline, may be preferred initially if the patient is unwilling to take injections or if the GH elevations are relatively modest (< 10 ng/mL). Biochemical cure should be assessed by measurement of GH (which can be performed 2 hours after an octreotide injection) and IGF-1 concentrations. The goal of treatment include reduction of of GH below 2 ng/mL and reduction of IGF-1 into the normal range. In patients who do not reach these goals, the dose or frequency of injection of the somatostatin analogue or both should be increased. If such measures are unsuccessful, a dopamine agonist may be added to the medical regimen because some studies suggest that combination therapy may be more effective in select cases than octreotide therapy alone. If such measures are still unsuccessful, other options should be considered, including surgery, pituitary radiation, and medical treatment with investigational drugs.
生长抑素类似物可与生长抑素受体亚型2和5结合,多巴胺激动剂则对D2受体具有特异性,二者均已用于治疗肢端肥大症。这两类药物中的每一种都包含几种化合物,它们在作用持续时间、疗效和副作用方面存在差异。尽管生长抑素类似物可降低大多数患者的生长激素(GH)水平并缓解症状,使60%至65%的患者的胰岛素样生长因子-1(IGF-1)水平恢复正常,但肿瘤缩小仅见于40%的患者。文献中的证据支持将这些药物用作肢端肥大症患者的二线治疗,这些患者已经接受了手术,但GH水平仍然升高(口服葡萄糖耐量试验期间高于2 ng/mL),无论IGF-1浓度是否高于年龄对应的正常上限。此外,对于拒绝手术的患者以及手术候选不佳的患者,也需要进行药物治疗。存在争议的问题是,药物治疗是否应作为肢端肥大症患者的初始治疗选择。目前,尚无前瞻性随机试验的数据来比较手术与生长抑素类似物作为新诊断肢端肥大症患者一线治疗的效果。非随机研究的有限数据表明,生长抑素类似物在从未接受过治疗的患者中,约三分之二的患者能够长期有效抑制GH并将IGF-1降至正常范围。目前仍存在共识认为,分泌GH的微腺瘤患者应接受手术切除,因为经验丰富的神经外科医生实现完全治愈的可能性很高,至少为70%或更高。与药物治疗相比,成功的手术治疗具有完全切除肿瘤的优势,尽管IGF-1和GH水平可能正常,但药物治疗很少能使肿瘤缩小超过50%。对于大腺瘤患者,如果其大小和位置提示完全切除的机会为40%或更低,则应考虑将生长抑素类似物作为初始治疗的一种选择。对于此类患者的另一种选择是手术减瘤后进行药物治疗,因为理论上手术减瘤后使用较低剂量的药物治疗可能实现生化治愈。这些方法的成本效益尚未确定。一旦决定开始药物治疗,就必须在多巴胺激动剂和生长抑素类似物之间做出选择。大多数证据表明,生长抑素类似物比多巴胺激动剂更有效,因此是首选治疗方法。在某些特定患者中,如果患者不愿意接受注射或GH升高相对较小(<10 ng/mL),则最初可能首选多巴胺激动剂,尤其是长效激动剂卡麦角林。应通过测量GH(可在注射奥曲肽2小时后进行)和IGF-1浓度来评估生化治愈情况。治疗目标包括将GH降至2 ng/mL以下,并将IGF-1降至正常范围。对于未达到这些目标的患者,应增加生长抑素类似物的剂量或注射频率,或两者同时增加。如果这些措施不成功,可在药物治疗方案中添加多巴胺激动剂,因为一些研究表明,联合治疗在某些特定情况下可能比单独使用奥曲肽治疗更有效。如果这些措施仍然不成功,则应考虑其他选择,包括手术、垂体放疗以及使用研究性药物进行治疗。