Review articleNew medical therapies of acromegaly
Introduction
Acromegaly is a chronic disfiguring disease characterized by growth hormone (GH) and consequently insulin-like growth factor-I (IGF-I) hypersecretion causing also development of cardiovascular, respiratory, metabolic, skeletal and neoplastic complications with significant impact on patient's quality of life and survival [1], [2]. Treatment of acromegaly aims at normalizing GH and IGF-I hypersecretion, controlling tumor growth, improving symptoms and comorbidities and decreasing mortality [3]. Available therapeutic approaches are neurosurgery, medical management and radiotherapy [3], [4]. Traditionally, transsphenoidal surgery is the gold standard for treatment of acromegaly since it is the only therapeutic approach ideally able to immediately resolve GH hypersecretion by removal of pituitary tumor [5]. However, neurosurgery is able to cure the disease only in about half of the patients. Indeed, the success of surgery is closely related to experience of neurosurgeon [6] as well as to the size and invasiveness of pituitary tumor [7]. When performed by a dedicated and experienced pituitary neurosurgeon conducting at least 50 pituitary operations per year, surgical removal provides biochemical control in 75–95% of patients with microadenoma [6], [7]. However, the diagnosis of acromegaly is still delayed [8] and most of acromegaly patients have a pituitary macroadenoma, often with suprasellar extension. In these circumstances, even when surgery is performed by a qualified neurosurgeon and by more modern endoscopic techniques [9], [10], the large size and invasiveness of the adenoma are usually the cause of the incomplete recovery of disease. When neurosurgery is not curative, control of GH hypersecretion can be achieved by adjuvant medical therapies, including dopamine agonists (DAs), somatostatin receptor ligands (SRLs) and pegvisomant [11]. Radiotherapy (RT) is generally used as third line therapy in patients who have residual tumor in areas that may lead to neurological complications [3].
Indeed, treatment of acromegaly may be a challenge since a multimodal treatment is often required [12]. However, despite all efforts, therapeutic options currently available do not induce biochemical remission of disease in all patients [13]. Therefore, in recent years, research has focused on new therapeutic approaches by either evolution of traditional therapeutic protocols or development of new molecules with different profiles of activity [13], [14].
This article will review the new medical approaches in the treatment of acromegaly. Full-text articles in English language were selected from a PubMed search spanning 1984- July 2016, for keywords including ‘somatostatin’, ‘somatostatin analogs,’ ‘pasireotide,’ and ‘acromegaly therapy’. Trial.gov was also consulted searching for new molecules with unpublished data. Reference lists in selected papers were also used to broaden the search.
Section snippets
Evolution of therapies with first generation SRLs
First generation SRLs, octreotide long-acting release (LAR) and lanreotide Autogel, are the first line medical therapy of acromegaly (Table 1) [11]. In clinical trials, these drugs normalized GH and IGF-1 in half to two thirds of the patients [15]. However, the real-life effectiveness resulted to be lower than the efficacy observed in the pre-designed trials. In fact, databases reported a biochemical control of acromegaly in < 50% of patients treated with SRLs [16], [17]. Such a discrepancy,
Multiligand SRLs
Five distinct SSTRs 1–5 were identified and cloned [43]. The pathophysiological rationale established a posteriori for using octreotide and lanreotide in acromegaly is their specificity for SSTR-2 which has a major role in regulating GH secretion and tumor growth in pituitary GH-secreting adenoma [44], [45]. However, this peculiarity of octreotide and lanreotide may become a weakness in some patients. In fact, GH-secreting adenomas express other SSTRs, such as SSTR5, SSTR3 and SSTR1 [46], which
New targeted therapy
Current marketed molecules, either as mono- or combination therapies, do not achieve a complete remission of the disease despite being directed on central and peripheral targets (SSTRs and GH receptor) [13]. Furthermore, real-life practice has highlighted possible occurrence of resistance (partial/total) to SRLs and escape on pegvisomant. This last molecule has generated considerable debate in the scientific literature, considering that in pivotal trials biochemical remission was found in near
Conclusions
Octreotide LAR and lanreotide Autogel have been the mainstay of medical treatment in acromegaly with a consolidated favorable benefit versus risks profile. However, several patients treated with these first generation SRLs do not achieve the strict biochemical control required to improve comorbidities and normalize mortality. Therefore, new medical therapies of acromegaly have been developed in order to overcome the total or partial resistance to SRLs determined by several factors either
Conflict of interest statement
G.M. received consultant fees from Novartis Farma and Ipsen and received lecture fee from Ipsen. A.G. is a consultant for Ipsen, Novartis, and Pfizer. F.M., M.D. and S.F. have nothing to disclose.
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2022, International Journal of PharmaceuticsCitation Excerpt :The disease is characterized by excessive secretion of growth hormone (GH), which leads to the development of acromegaly or pituitary cancer (Chanson and Salenave, 2008; Frara et al., 2016). The GH is produced in a pulsatile fashion via somatotroph cells of the pituitary gland, where an imbalance of GH level in the body stimulates the hepatic secretion of insulin-like growth factor-1 (IGF-1) (Maffezzoni et al., 2016). Both of these hormones, GH and IGF-1, are further responsible for extra-somatic growth, which is a prominent characteristic of pituitary adenoma (Frara et al., 2016; Rai et al., 2015).
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