Frara Stefano, Maffezzoni Filippo, Mazziotti Gherardo, Giustina Andrea
Endocrinology, University of Brescia, Brescia, Italy.
Endocrinology, University of Brescia, Brescia, Italy.
Prog Mol Biol Transl Sci. 2016;138:63-83. doi: 10.1016/bs.pmbts.2015.10.015. Epub 2016 Jan 6.
Acromegaly is an insidious disorder characterized by excess secretion of growth hormone (GH) and elevated circulating levels of insulin-like growth factor-I (IGF-I), generally caused by a pituitary adenoma. It is a rare disease associated with an average 10-year reduction in life expectancy due to metabolic, cardiovascular, and cerebrovascular comorbidities and reduced quality of life caused by paresthesias, fatigue, osteoarthralgia, or bone fractures. In 2000, Cortina Consensus Conference established general criteria for diagnosis and biochemical control of acromegaly, which have been revised in recent years, adapting them to emerging clinical evidences as well as the evolving assay techniques. Authors have proposed a binary definition of cure for acromegaly, where both GH and IGF-I are important determinants: the former is more linked to the presence of residual adenomatous tissue, while the latter to the peripheral activity of the disease. Control of tumor growth and complications is also an essential goal of treatment. Surgical, medical, and radiotherapy approaches are all valid alternatives. The surgical option is, however, unsuccessful in about 50% of patients. Somatostatin analogs (SRLs), octreotide LAR, and lanreotide ATG can inhibit cell growth, besides their beneficial effects on GH hypersecretion and on most comorbidities. Pasireotide is a new multireceptor-targeted SRL with reported superior biochemical efficacy to octreotide, due to higher affinity for SSTR-5, but potentially causing detrimental effects on glucose homeostasis. Pegvisomant could be a valid choice in all patients resistant to SRLs. It is a competitive GH antagonist, which efficaciously blocks IGF-I production, inhibiting the dimerization of GH receptor. Normal IGF-I levels represent, therefore, its only relevant efficacy endpoint, while only few cases of tumor growth on pegvisomant have been reported, so far.
肢端肥大症是一种隐匿性疾病,其特征是生长激素(GH)分泌过多以及循环中的胰岛素样生长因子-I(IGF-I)水平升高,通常由垂体腺瘤引起。它是一种罕见疾病,由于代谢、心血管和脑血管合并症,平均预期寿命缩短10年,并且感觉异常、疲劳、骨关节炎或骨折导致生活质量下降。2000年,科尔蒂纳共识会议制定了肢端肥大症的诊断和生化控制的一般标准,近年来这些标准已得到修订,使其适应新出现的临床证据以及不断发展的检测技术。作者提出了肢端肥大症治愈的二元定义,其中GH和IGF-I都是重要的决定因素:前者与残留腺瘤组织的存在更相关,而后者与疾病的外周活性相关。控制肿瘤生长和并发症也是治疗的重要目标。手术、药物和放射治疗方法都是有效的选择。然而,手术方案在约50%的患者中不成功。生长抑素类似物(SRLs)、奥曲肽长效释放剂和兰瑞肽ATG除了对GH分泌过多和大多数合并症有有益作用外,还能抑制细胞生长。帕西瑞肽是一种新的多受体靶向SRL,据报道其生化疗效优于奥曲肽,因为它对SSTR-5的亲和力更高,但可能对葡萄糖稳态产生有害影响。培维索孟可能是所有对SRLs耐药患者的有效选择。它是一种竞争性GH拮抗剂,能有效阻断IGF-I的产生,抑制GH受体的二聚化。因此,正常的IGF-I水平是其唯一相关的疗效终点,而迄今为止,仅有少数关于培维索孟治疗后肿瘤生长的病例报道。