Dan He
Qinyi Wang2
Zhifeng Sheng
Guohua Li- 1Department of Endocrinology and Metabolism, Xiangtan Central Hospital (The Affiliated Hospital of Hunan University), Xiangtan, China
- 2Health Management Center, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Clinical Medicine Research Center for Intelligent Management of Chronic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
Acromegaly is a chronic endocrine disorder characterized by excessive secretion of growth hormone (GH), predominantly caused by pituitary adenomas. Despite advancements in neurosurgical techniques, the surgical remission rates for invasive macroadenomas or giant adenomas remain unsatisfactory. Therefore, multimodal treatment strategies, including preoperative medical therapy (POMT), have been implemented to improve patient outcomes. Among these, first-generation somatostatin receptor ligands (fg-SRLs) have been the most extensively studied preoperative agents; however, their clinical efficacy in enhancing postoperative remission remains controversial. In recent decades, ongoing research into novel drugs and molecular targets are reshaping the therapeutic landscape of POMT. Beyond traditional clinical models and functional assays, the integration of advanced imaging modalities and molecular biomarkers promises to refine patient stratification, particularly for individuals with suboptimal responses to transsphenoidal surgery (TSS). Furthermore, novel SRL formulations and the identification of new molecular targets could further expand the therapeutic landscape of POMT. In this narrative review, we systematically summarize the latest research advancements in POMT for acromegaly and discusses potential therapeutic strategies and persisting obstacles in this field.
1 Introduction
Acromegaly is a rare and insidious disease, typically caused by pituitary tumors that continuously secretes excess growth hormone (GH). This disorder elevates the risk of complications, including left ventricular hypertrophy, hypertension, diabetes, osteoporosis, and sleep apnea, which significantly impair the patient’s quality of life and lifespan (1). Transsphenoidal microsurgery (TSS) is the preferred treatment of choice for most patients with active acromegaly. However, based on the 2000 remission criteria, the recurrence rate of acromegaly in patients treated exclusively with TSS is exceedingly high (2, 3). With advancements in biochemical testing techniques, the 2010 guidelines established more stringent biochemical remission criteria (4). Under these criteria, the surgical remission rate for microadenomas in experienced centers ranges from 56% to 100%, while the remission rate for large adenomas, which constitute 77% of GH-secreting tumors, is only between 27.8% and 61% (5–8). In cases of large adenomas or those significantly invading the cavernous sinus (CSI), the cure rate remains relatively low (9). Therefore, medical therapy and radiotherapy have become important adjuncts to surgical treatment. To improve the remission rate of acromegaly, some clinicians have proposed implementing preoperative medical therapy (POMT) in patients with anticipated low rates of TSS remission (10–13). Recent consensus guidance indicates that POMT may be considered in carefully selected patients (for example, when surgical cure is unlikely, surgery will be substantially delayed, or peri-operative risk is high), whereas routine use to enhance postoperative remission is not recommended (14). Advances in imaging, molecular biomarkers, and drug development have deepened the understanding and optimized the management of acromegaly (15). Novel imaging approaches and biomarker studies offer potential for predicting POMT responsiveness, with evidence linking POMT to favorable modulation of markers related to apoptosis and tumor invasiveness (15, 16). This narrative review aims to summarize the new evidence for POMT and outlines future directions to support the development of individualized treatment strategies for acromegaly.
2 Literature search strategy
A narrative review of the literature was conducted to summarize the current evidence on POMT for acromegaly. The search was performed using the following databases: PubMed, EMBASE, and Web of Science. Key search terms included “preoperative medical therapy,” “acromegaly,” “somatostatin receptor ligands,” “growth hormone receptor antagonists,” and “dopamine agonists.” The literature search covered studies published up to June 2025. No specific restrictions were applied regarding study design or publication type, but the focus was on studies directly related to the clinical management of acromegaly and the application of POMT.
3 The concept of POMT for acromegaly
The exploration of POMT for acromegaly commenced over 40 years ago (17). At that time, only one-third of patients with large adenomas attained surgical remission, and nearly all patients with tumors involving the parasellar region failed to be cured through surgery (17, 18). Meanwhile, researchers suggested preoperative treatment with bromocriptine for prolactinomas, as it inhibits prolactin secretion and induces tumor shrinkage in most prolactin-secreting pituitary tumors (19). This raised the possibility of applying POMT to pituitary GH adenomas with poor surgical outcomes. Barkan AL et al. first evaluated POMT in ten previously untreated patients with invasive large adenomas, demonstrating that preoperative somatostatin receptor ligands (SRLs, e.g., SMS 201-995) markedly reduced GH and IGF-1 levels and resolved or diminished parasellar and cavernous sinus invasion (17). This approach achieved an 80% short-term postoperative remission rate, compared with 31% in a matched surgical-only cohort (17). Subsequent studies have increasingly focused on using POMT to optimize preoperative biochemical control, reduce surgical risks, facilitate complete tumor resection, and improve postoperative remission outcomes (13, 20).
4 Research progress on POMT for acromegaly
The pharmacological treatment options for acromegaly can be categorized into three main groups: somatostatin receptor ligands (SRLs), which are recommended as the first-line treatment for patients who are not candidates for surgery; growth hormone receptor (GH) antagonists, which serve as adjunctive therapy for severe cases beyond the first-line treatment; and dopamine agonists (DAs), which are used as adjunctive therapy for mild cases (15, 21, 22). In the field of POMT research, first-generation somatostatin receptor ligands (fg-SRLs) are the most extensively studied, whereas data for other agents are scarce and provide only limited support for their use in treatment strategies (Table 1).
Table 1. Comparative overview of drugs available for POMT in acromegaly.
4.1 SRLs
SRLs act by binding to somatostatin receptor subtypes (SSTRs), inhibiting adenylate cyclase, lowering cyclic adenosine monophosphate (cAMP) and intracellular calcium levels, and suppressing GH secretion (23). SSTR2 and SSTR5 mediate antiproliferative effects via tyrosine phosphatase activation and ERK1/2 inhibition, while SSTR2 and SSTR3 contribute to apoptosis (24, 25). Additionally, since hepatocytes also express SSTR2 and SSTR3, SRLs exert peripheral inhibitory effects on the GH-IGF-1 axis (26). Although natural somatostatin can bind to five different SSTRs, SRLs exhibit varying affinities for SSTR1-5. First-generation SRLs, such as octreotide and lanreotide, primarily bind to SSTR2, with a lower affinity for SSTR5 (27). The novel multi-receptor ligand SRL pasireotide binds to SSTR1, 2, 3, and 5, with a binding affinity for SSTR5 that is 39 times higher than octreotide and 106 times higher than lanreotide, as well as a 30-fold higher affinity for SSTR1 compared to octreotide and 19-fold compared to lanreotide (28, 29). Clinically, pasireotide achieves superior suppression of GH and IGF-1 compared with fg-SRLs (30–32).
Currently, the primary drugs used for POMT in acromegaly are fg-SRLs, while the second-generation long-acting SRL, pasireotide, has been studied only in small sample studies from Taiwan and case reports from Japan (33, 34). This suggests that pasireotide requires larger, more comprehensive clinical trials to assess whether it could be a potential treatment option for invasive and fg-SRLs-resistant sparsely granulated adenomas (SGAs).
4.2 GH receptor antagonists
Pegvisomant is a pegylated recombinant human GH analogue that treats acromegaly by directly inhibiting the synthesis of IGF-I in the liver. This drug does not act at the pituitary level and therefore does not suppress tumor growth. Initially, clinicians were concerned that reducing IGF-I levels might lead to an increase in the volume of GH-secreting adenomas. However, since tumor growth is typically observed in younger patients with higher GH levels, the 5–10% increase in tumor volume observed during pegvisomant monotherapy is considered more likely to reflect the natural progression of aggressive tumors or a rebound effect after discontinuing prior SRL treatment (35–38). On the other hand, pegvisomant has been demonstrated to effectively control IGF-I levels while improving glucose metabolism (39, 40), obstructive sleep apnea (41), and arrhythmiasin acromegaly patients (42), with neutral or potentially beneficial effects on cardiovascular outcomes (43). Currently, only two cases have been reported involving the preoperative use of pegvisomant (44). As the accessibility and cost of this drug improve in the future, clinicians may consider incorporating it into POMT for acromegaly.
4.3 DAs
DAs can bind to dopamine receptor subtype 2 in GH adenomas, reducing the secretion of GH and IGF-1, and inhibiting tumor cell proliferation (45). A small sample study showed that preoperative treatment with cabergoline improved biochemical control in acromegaly patients, with tumor volume changes mainly observed in GH/prolactin co-secreting tumors, and less frequently in tumors that solely secrete GH (46, 47). Although DAs are not an ideal choice for POMT in acromegaly, due to their cost-effectiveness and availability, they may still be explored as part of preoperative combination therapy for patients with incomplete responses to SRLs.
5 The clinical treatment benefits of fg-SRLs
Among POMT strategies for acromegaly, fg-SRLs are the most extensively studied, with agents such as octreotide and lanreotide demonstrating potential clinical benefit (Table 2). Evidence suggests that a 3–6 month course of fg-SRLs prior to surgery can significantly alleviate common symptoms of acromegaly (48), lower GH and IGF-1 levels (11, 49, 50), and induce a tumor volume reduction of more than 20% in approximately 50% of treatment-naive patients (51–56). Additionally, fg-SRLs have shown beneficial effects on cardiac rhythm and ejection fraction in patients without left ventricular hypertrophy, as well as improvements in lipid profile, blood pressure, and glycemic control (48, 57). However, no significant impact has been observed on immediate postoperative complications or perioperative mortality (51, 58–61). Furthermore, several aspects remain debated, including whether preoperative fg-SRLs influence surgical outcomes by altering tumor consistency, reduce anesthetic risks, or shorten hospitalization (48, 51, 57, 58, 60–62). Further research is needed to clarify their impact on postoperative remission, potential anti-tumor effects, and health economics.
Table 2. Comparative summary of studies on POMT for acromegaly.
5.1 Anti-tumor effect
Evidence indicates that preoperative short-acting octreotide can reduce tumor size within 8 weeks (50). In invasive large adenomas, preoperative lanreotide treatment led to a significantly greater tumor volume reduction in patients with short-term remission (60). As pituitary tumor growth reflects the interplay of proliferation, apoptosis, and ischemic or hemorrhagic events, further studies have explored the anti-tumor mechanisms of POMT.
Wasko and colleagues observed that preoperative lanreotide treatment could induce apoptosis in GH-secreting adenoma cells (63). Subsequent studies revealed that patients receiving fg-SRLs treatment showed a significant increase in in situ DNA end labeling-positive cells, which correlated positively with the duration of preoperative treatment (63). Similarly, two retrospective studies reported a positive correlation between both the duration and cumulative dose of POMT and the apoptosis index in patients with acromegaly (64, 65). Dagistanli FK et al. reported a significant increase in caspase-3–positive cells in acromegaly tumor tissue, along with a marked decrease in survivin and beclin-1 immunopositivity, and an elevated expression of autophagy-related protein 5 (66). Previous studies have demonstrated that the mesenchymal marker RORC is associated with E-cadherin expression and epithelial-mesenchymal transition (EMT) in acromegaly, both of which are linked to increased tumor size and invasiveness (67–71). Gil et al. investigated the effect of POMT on tumor invasiveness markers and found elevated RORC expression in patients receiving preoperative fg-SRLs (72). Notably, higher RORC levels were observed in those who achieved remission and were significantly correlated with a greater reduction in postoperative IGF-1 levels (72).
Collectively, these studies suggest that fg-SRLs may induce tumor shrinkage in acromegaly by promoting tumor cell apoptosis and inhibiting proliferation. In some patients, the antiproliferative effect of octreotide appears to occur independently of its antisecretory action (50, 53). For invasive large adenomas (Knosp grades 3-4) without visual involvement or pituitary apoplexy, if tumor growth is not progressive after fg-SRLs treatment, extended POMT durations (e.g., 12 months) at maximum tolerated doses may be considered to promote tumor shrinkage, facilitate surgical resection, and improve remission rates.
5.2 Improve remission rates
Reducing preoperative IGF-1 and GH levels and shrinking tumor volume with fg-SRLs therapy has long been expected to improve surgical remission rates (11, 73). However, even under the relatively lenient 2000 remission criteria, evidence in GH-secreting pituitary adenomas has been inconsistent, largely due to heterogeneity in study design, sample size, remission definitions, follow-up duration, tumor characteristics, and preoperative treatment regimens (48, 60, 62, 74–76).
Early small-cohort studies may have lacked statistical power to detect significant differences (50, 74, 77), while contemporaneous larger cohorts reported opposite (10). Subsequent retrospective analyses, including a single-center series of 358 patients (78) and multi-center studies (79), confirmed that POMT improved postoperative remission, with case–control data consistently showing benefits for large adenomas (48, 51, 60). Meta-analyses further supported these findings, particularly in patients with suboptimal surgical prognosis (80). To avoid the influence of the lingering effects of preoperative fg-SRLs therapy, these studies delayed postoperative evaluations. However, assessing hormone control 3–4 months post-surgery is generally considered the minimum safe period to eliminate the effects of fg-SRLs. Data collected more than a year post-surgery provides a clearer indication, as it can exclude any residual effects of preoperative fg-SRLs treatment, offering more clinically relevant insights into cure and remission rates (81). Subsequent studies on long-acting fg-SRLs for preoperative treatment have shown less favorable results for long-term remission, with both randomized controlled trials and high-quality meta-analyses demonstrating limited benefits (75, 82). In 2010, revised guidelines introduced more stringent remission criteria, under which long-acting fg-SRLs preoperative treatment was associated with significantly higher long-term remission rates compared to surgery alone (61), and multivariable analysis indicated a significant correlation between POMT and long-term remission (83).
A retrospective study on antitumor characteristics categorized GH adenoma patients into four groups based on tumor size and invasiveness (49). The study found that short-acting octreotide preoperative therapy significantly increased surgical remission rates in the aggressive large adenoma group (49). However, no differences were observed in overall remission rates in the microadenoma group or the non-resectable large adenoma group compared to the control group (49). The results of the subgroup analysis offered valuable insights for future research: tumor size and invasiveness should be considered when selecting and matching patients for POMT. As the Knosp grading system becomes more widely used, researchers have focused on evaluating the benefits of preoperative fg-SRLs therapy on postoperative remission rates in GH adenomas with different Knosp grades. A randomized controlled trial found that acromegaly patients with Hardy-Knosp grades III-IV benefited significantly from POMT compared to those with Hardy-Knosp grade V (48). Cohort studies demonstrated that POMT significantly improved remission rates for invasive large adenomas with Knosp grades 1-3, increasing from 37.3% to 56.4% (78). However, it did not enhance remission rates for microadenomas or large adenomas with Knosp grades 0-2 (84). Additionally, POMT showed no benefit in postoperative remission for invasive large adenomas with Knosp grade 4 (50, 78).
In terms of drug selection and treatment duration, early studies used short-acting octreotide administered three times daily, with daily doses ranging from 100 to 1500 µg and treatment durations varying from 2 weeks to 39 months (10, 49, 50, 77). Tumor reduction in pituitary GH adenomas reached near its maximum after 3–4 months of high-dose short-acting octreotide therapy (50). This finding provided a reference for the duration of POMT, and subsequent randomized controlled trials typically designed treatment durations of 3–6 months (48, 51, 60, 75). With the development of long-acting fg-SRLs, the treatment regimen for POMT has progressed from octreotide microspheres and lanreotide acetate to the current formulations of octreotide microspheres and lanreotide acetate long-acting injections, with dosing schedules of 20–30 mg every 28 days and 60–120 mg, respectively (83, 85, 86). A recent study further revealed that preoperative treatment with ≥30 mg of octreotide or ≥90 mg of lanreotide acetate long-acting injection significantly improved long-term surgical remission rates compared to lower-dose treatments or untreated patients (61). A multicenter study in Poland administered 6–12 months of preoperative octreotide microsphere therapy for large adenomas to achieve maximal reduction in GH and IGF-1 concentrations (85). During the treatment period, 49.1% of large adenomas experienced a ≥20% reduction in volume, and GH and IGF-1 levels decreased by 49% and 40%, respectively (85). The 12-month POMT treatment was found to be safe and well-tolerated (85). However, another study showed no superior results in tumor volume reduction and endocrine control compared to a concurrent large-scale study conducted in China, which used 3 months of preoperative octreotide microsphere therapy for GH adenomas (86). Unfortunately, neither of these studies directly compared the treatment duration of octreotide microsphere preoperative therapy.
For invasive large adenomas with Knosp grade 4, multimodal therapy remains standard. In contrast, Knosp grades 1–3 warrant careful POMT consideration, as high-dose SRLs may enhance SSTR5 binding, upregulate SSTR2, and promote greater tumor shrinkage (80). Given that the most pronounced volumetric response occurs within the first year, large-scale prospective trials are needed to define the optimal dosing and duration for maximizing surgical outcomes (54).
5.3 Reducing medical costs
Colao et al. explored the cost-effectiveness of short-acting octreotide POMT, finding it offers a better cost-benefit ratio than surgery alone (57). Two subsequent studies confirmed that, in centers with suboptimal surgical outcomes, preoperative fg-SRL treatment not only improved surgical results but also provided long-term cost savings (87, 88). One study focused solely on pharmacoeconomic costs (87), while the other employed a dynamic Markov model to comprehensively assess costs, including diagnostics, treatment (surgery, medication, or radiotherapy), complications, and disease monitoring (88). However, an opposing study, with a shorter evaluation period and smaller sample size, found no significant cost-effectiveness advantage for POMT (89).
In summary, the use of fg-SRLs for preoperative treatment in acromegaly has gained continued attention and influenced clinical practices in several countries (90). While debates persist, the benefits of POMT are becoming clearer, particularly as study sample sizes grow, study designs improve, remission criteria and follow-up periods are standardized, and participant characteristics are refined. This trend is especially evident in patients who are unlikely to achieve remission post-surgery or have surgical contraindications, as well as those treated in centers with suboptimal surgical outcomes.
5.4 Preoperative SRLs in patients with airway/anesthetic risk
Patients with acromegaly frequently have airway abnormalities and obstructive sleep apnea (OSA), which increase the risk of difficult laryngoscopy and traumatic intubation (41). In selected high-risk patients (e.g., marked oropharyngeal soft-tissue thickening, macroglossia, or severe OSA), short-term preoperative SRLs therapy may be considered to reduce soft-tissue edema and optimize peri-anesthetic conditions (41). Notably, in a comparative series, SRLs pretreatment improved the Cormack–Lehane laryngoscopic grade, yet the overall rate of difficult intubation did not differ from surgery-alone controls, indicating that airway benefits may not translate into fewer difficult intubations at the cohort level and should be individualized to patients at highest risk (76).
6 Identifying candidates for preoperative fg-SRLs therapy
Many studies have investigated clinical and imaging predictors of postoperative biochemical remission to assist in preoperative decision-making. For patients assessed to have a low chance of surgical cure based on clinical parameters such as age, sex, preoperative biochemical markers, tumor size, CSI, and bilateral internal carotid artery distance (91–94), multi-modal treatments, including POMT, should be considered, especially for those treated at surgical centers with less experience (95–97).
However, not all patients with low expected TSS remission rates are suitable for POMT. Evidence shows that up to 45% of acromegaly patients have poor or no response to fg-SRLs, potentially due to varying expression of SSTR subtypes in tumors (98, 99). While SSTR phenotype and tissue patterns predict SRL treatment efficacy, they do not directly guide preoperative decisions (100). Therefore, clinical pre-stratification methods are needed to identify patients most likely to benefit from fg-SRLs-based POMT, enabling personalized and precise treatment (Table 3).
Table 3. Preoperative assessment strategies for predicting responsiveness to fg-SRLs in patients with acromegaly.
6.1 Clinical baseline information predictors for preoperative fg-SRLs therapy
Certain preoperative clinical information can predict the response to fg-SRLs treatment. Younger male patients generally exhibit poorer responses to SRLs (101), while factors such as lower GH levels at diagnosis, smaller tumor size, and the absence of cavernous sinus invasion are closely linked to better hormonal responses to SRL treatment (56). A maximum tumor diameter of 2 cm is a strong predictor of both biochemical response and tumor shrinkage, and is correlated with the proportion of SG adenomas and Ki-67 expression (63). A meta-analysis using multivariate regression models on 622 patients from two European cohorts found that baseline IGF-1 was the best predictor of biochemical response to fg-SRLs, followed by body mass index (BMI) (102). Furthermore, combining diagnostic age, previous surgery, and tumor size helped identify non-responders (102).
Some of these predictive factors also serve as prognostic indicators for surgical outcomes after preoperative fg-SRLs treatment. A post-hoc analysis of the PRIMARYS study found that older age, female sex, and lower baseline IGF-I levels were associated with a higher likelihood of long-term biochemical control following long-acting SRL injection (103). Tumor invasiveness is also significantly related to both short-term and long-term remission benefits from POMT, and POMT is recommended as first-line treatment for patients with cavernous sinus invasion (51, 104, 105).
6.2 Innovative imaging technology for preoperative fg-SRLs therapy
With the widespread use of magnetic resonance imaging (MRI) in the diagnostic imaging of pituitary tumors, researchers have found that tumors with low T2-weighted signal on MRI typically respond better to SRLs than those with equal or high signal (106–108). This is explained by the correlation between low T2 signal and high expression of SSTR2A on the cell membrane of densely granulated (DG) tumors (109). The expression of SSTR2A is higher in DG tumors than in sparsely granulated (SG) tumors, and patients with SSTR2A-positive tumors show a better response to fg-SRLs, making DG tumor patients respond significantly better to this treatment (100). In recent years, researchers have further explored quantitative T2-weighted MRI techniques, such as T2 homogeneity ratios and relative signal intensities, to predict tumor volume reduction >20%, combining these methods with qualitative T2-weighted MRI to better predict histological patterns (110). New radiomics methods, such as quantitative texture analysis, have also been applied to assess the response to fg-SRLs (111). In terms of functional imaging, initial explorations of 111Indium-pentetreotide scintigraphy ± SPECT (octreoscan) and 68Gallium-DOTATE PET/CT have not demonstrated clear clinical effectiveness in predicting SRL response (112, 113).
6.3 Functional testing for preoperative fg-SRLs therapy
Early studies on the use of short-acting octreotide in preoperative treatment aimed to assess the effectiveness of fg-SRLs therapy through functional tests. Over the following decades, a series of investigations were conducted, though methodological variations were present. Most studies involved a single subcutaneous injection of 100 µg of octreotide, with some using alternative dosages or multiple daily injections. The timing of blood sampling after administration was not standardized, and evaluation criteria varied, leading to differing conclusions.
Several studies have suggested that the octreotide suppression test is closely correlated with a reduction in preoperative serum GH levels and can predict the biochemical response after octreotide treatment (50, 114, 115). This appears to be a key factor for achieving postoperative biochemical control in POMT patients. However, the effect of the octreotide suppression test on tumor volume and postoperative remission rates remains debated. Notably, a positive response to either octreotide or bromocriptine suppression tests was not associated with tumor reduction (50, 53). However, a positive response to both tests was significantly correlated with tumor shrinkage (50). The octreotide suppression test demonstrated no predictive value in relation to postoperative remission. Nevertheless, Annamalai AK et al. found that GH reduction after a 100µg subcutaneous octreotide injection correlated with changes in GH, IGF-1, and tumor volume after 6 months of lanreotide therapy, and was predictive of short-term postoperative remission (116). Despite lacking specific sampling time points for GH nadir, responders showed a GH reduction of over 69%, higher than the criteria used in other studies (116). Even patients categorized as non-responders showed GH reductions of 29.2% and 30.1%, respectively (116). These findings suggest the need for further exploration of the octreotide suppression test evaluation criteria.
Studies examining the effects of various drugs have demonstrated that the octreotide suppression test is only capable of predicting the long-term efficacy of short-acting octreotide and offers no predictive value for lanreotide acetate (114). Within the first six months of treatment, short-acting octreotide leads to a more rapid and significant reduction in IGF-I and GH compared to lanreotide acetate. Therefore, short-acting octreotide is recommended for preoperative short-term treatment, while lanreotide acetate is preferred for long-term postoperative treatment (114). However, several meta-analyses on preoperative SRL therapy have shown that lanreotide is as effective as octreotide in improving short-term postoperative remission rates (116, 117). These studies included short-acting octreotide, lanreotide acetate, and octreotide microspheres. With advances in acromegaly treatment, octreotide microspheres and long-acting lanreotide acetate are increasingly used in POMT, providing valuable insights for clinical practice. The findings from these meta-analyses may provide further guidance for clinical practice.
Additionally, evidence suggests that GH reduction after the octreotide suppression test is significantly greater in Knosp grade 3–4 GH adenomas compared to grade 0-2 (50). Whether the same dosing methods and evaluation criteria should be applied to tumors with different levels of invasiveness, along with the integration of new imaging techniques and functional test results to predict the effects of preoperative SRLs therapy, remains a key area for future research.
6.4 Molecular biomarkers for preoperative fg-SRLs therapy
In addition to SSTR2 and the granule pattern, several molecular biomarkers can predict the response to SRLs. Among them, E-cadherin has garnered significant attention, as its loss is a key event in EMT and is associated with a lack of SRLs response in tumors (71). The mesenchymal marker Snail family transcriptional repressor 1 (SNAI1), a direct inhibitor of E-cadherin, also plays a crucial role as a transcription factor in EMT regulation (118). Gil et al. found that adenomas with extrapituitary growth expressed higher levels of SNAI1 and were the first to report a relationship between SNAI1 expression and poor SRLs response (72). Other molecular biomarkers, including RORC, β-arrestins expression, aryl hydrocarbon receptor interacting protein, and Survivin, have also been identified as potential preoperative predictors of fg-SRLs response (118–120). Further research is expected to enable preoperative assessment of these biomarkers using methods like Next-Generation Sequencing (NGS) from blood samples to predict treatment response.
Based on these findings, it is evident that previous studies on whether POMT improves the ultimate outcomes of acromegaly have not assessed and differentiated SRL responders and non-responders before administration. Further comparisons are needed to evaluate the impact of preoperative integrated assessment and tailored SRL treatment on improving surgical remission rates in responsive patients. In this context, our study proposes a POMT flowchart to assist in making individualized treatment decisions (Figure 1). Although several molecular biomarkers (e.g., β-arrestin, E-cadherin) have been explored to differentiate responders from non-responders, robust and validated assays suitable for preoperative use are not yet available. Future work should develop externally validate preoperative biomarker panels and predictive models, and conduct multicenter, prospective comparative studies.
Figure 1. POMT workflow for acromegaly. *In surgical centers with experienced surgeons or those utilizing technologies such as neuronavigation, patients with suspected drug resistance based on fg-SRLs sensitivity assessments should ideally be treated surgically. Otherwise, POMT can be attempted, with prompt referral to an experienced surgical center for surgery if necessary. **Long-acting octreotide 20–30 mg every 28 days or long-acting lanreotide 60–120 mg every 28 days, starting with a low dose and adjusting dosing intervals and amounts based on evaluation results; ***Good response: Biochemical response (normalization of IGF-1 or ≥rF- reduction) and tumor size response (tumor shrinkage >20%); ****Drug resistance: Normalization of hormonal deficiency, tumor enlargement, or tumor shrinkage of less than 20% of baseline volume.
7 Clinical potential of new SRLs formulations for POMT
To improve remission rates in treatment-resistant patients and adherence in those intolerant to current therapies, novel formulations of existing SRLs are under development. As injectable SRLs remain the cornerstone of POMT, evaluating their new delivery forms is essential. Oral octreotide, a new formulation that combines octreotide with permeability enhancer technology, addresses issues like injection site pain, induration, and the inconvenience of hospital visits (121). It can improve patient adherence, enhance quality of life during treatment, and allow more flexible dosage adjustments (122). However, there are no reports yet on the tumor-shrinking effects of oral octreotide on pituitary tumors. Considering that improving biochemical control and reducing tumor volume are the main goals of preoperative SRLs therapy, further studies on its role in POMT may be required once data on tumor-shrinking effects are available. Additionally, the development of water-soluble co-solvents, FluidCrystal technology, needle-free solid dosage injectors, and intranasal formulations could improve patient adherence and the possibility of self-administration. These drugs are still in phase I-III clinical trials, and POMT-related studies will need to wait for data on their effects on biochemical control and tumor shrinkage before they can be considered for further development.
8 Conclusions and future perspectives
In conclusion, the treatment of acromegaly remains challenging, requiring multimodal therapies, including POMT, to improve patient prognosis. fg-SRLs, extensively studied for preoperative treatment, have shown benefits despite some controversy. The effects of these drugs on postoperative remission rates, anti-tumor activity, molecular biomarkers, and health economics continue to attract attention, with increasingly clear results, with clearer results emerging. Models incorporating various clinical factors and functional tests, especially the exploration of new imaging techniques and molecular biomarkers, may help identify patients who would benefit from POMT among those with suboptimal TSS outcomes. Patients with acromegaly frequently present with airway abnormalities and obstructive sleep apnea (OSA), contributing to difficult laryngoscopy/intubation. Guidelines suggest that preoperative SRLs may be considered in patients with severe pharyngeal thickening or OSA to reduce soft-tissue edema, improve OSA, and potentially lower intubation-related complications. Nevertheless, in a comparative series, SRLs pretreatment improved the Cormack–Lehane grade but did not reduce the overall rate of difficult intubation, underscoring that SRL use for airway optimization should be individualized to those at highest anesthetic risk. fg-SRLs remain the cornerstone of preoperative treatment, with most clinical studies currently focused on these agents. However, the routine use of growth hormone receptor antagonists (e.g., pegvisomant) and dopamine agonists (e.g., cabergoline) in POMT still lacks sufficient clinical evidence. While these therapies may hold potential in select cases, further research is necessary to establish their role in preoperative treatment.
Further research into whether POMT for SRL-sensitive patients improves surgical remission rates is needed. Furthermore, new formulations of existing SRLs and potential molecular targets may offer new insights and directions for POMT development in acromegaly.
Author contributions
DH: Validation, Writing – original draft, Data curation, Investigation, Conceptualization, Visualization. QW: Writing – review & editing, Validation. GL: Validation, Writing – review & editing. ZS: Formal analysis, Funding acquisition, Writing – review & editing, Data curation, Conceptualization.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the National Natural Science Foundation of China (No. 81870622), the Hunan Provincial Natural Science Foundation of China (No. 2023JJ30747), and the Hunan Provincial Clinical Medicine Research Center for Intelligent Management of Chronic Disease (No. 2023SK4042).
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Colao A, Grasso LFS, Giustina A, Melmed S, Chanson P, Pereira AM, et al. Acromegaly. Nat Rev Dis Primers. (2019) 5:20. doi: 10.1038/s41572-019-0071-6
2. Biermasz NR, van Dulken H, and Roelfsema F. Ten-year follow-up results of transsphenoidal microsurgery in acromegaly. J Clin Endocrinol Metab. (2000) 85:4596–602. doi: 10.1210/jcem.85.12.7042
3. Albarel F, Castinetti F, Morange I, Conte-Devolx B, Gaudart J, Dufour H, et al. Outcome of multimodal therapy in operated acromegalic patients, a study in 115 patients. Clin Endocrinol (Oxf). (2013) 78:263–70. doi: 10.1111/j.1365-2265.2012.04492.x
4. Jane JA Jr., Starke RM, Elzoghby MA, Reames DL, Payne SC, Thorner MO, et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab. (2011) 96:2732–40. doi: 10.1210/jc.2011-0554
5. Asha MJ, Takami H, Velasquez C, Oswari S, Almeida JP, Zadeh G, et al. Long-term outcomes of transsphenoidal surgery for management of growth hormone-secreting adenomas: single-center results. J Neurosurg. (2020) 133:1360–70. doi: 10.3171/2019.6.Jns191187
6. Taweesomboonyat C and Oearsakul T. Prognostic factors of acromegalic patients with growth hormone-secreting pituitary adenoma after transsphenoidal surgery. World Neurosurg. (2021) 146:e1360–e6. doi: 10.1016/j.wneu.2020.12.013
7. Araujo-Castro M, Pascual-Corrales E, Martínez-Vaello V, Baonza Saiz G, Quiñones de Silva J, Acitores Cancela A, et al. Predictive model of surgical remission in acromegaly: age, presurgical gh levels and knosp grade as the best predictors of surgical remission. J Endocrinol Invest. (2021) 44:183–93. doi: 10.1007/s40618-020-01296-4
8. Gadelha MR, Gadelha AC, and Kasuki L. New treatments for acromegaly in development. J Clin Endocrinol Metab. (2024) 109:e1323–e7. doi: 10.1210/clinem/dgad568
9. Sampedro-Nuñez M, Herrera-Martínez AD, Ibáñez-Costa A, Rivero-Cortés E, Venegas E, Robledo M, et al. Integrative clinical, hormonal, and molecular data associate with invasiveness in acromegaly: remah study. Eur J Endocrinol. (2024) 190:421–33. doi: 10.1093/ejendo/lvae045
10. Stevenaert A and Beckers A. Presurgical octreotide: treatment in acromegaly. Metabolism. (1996) 45:72–4. doi: 10.1016/s0026-0495(96)90088-8
11. Caron P, Bex M, Cullen DR, Feldt-Rasmussen U, Pico Alfonso AM, Pynka S, et al. One-year follow-up of patients with acromegaly treated with fixed or titrated doses of lanreotide autogel. Clin Endocrinol (Oxf). (2004) 60:734–40. doi: 10.1111/j.1365-2265.2004.02045.x
12. Feelders RA, Hofland LJ, van Aken MO, Neggers SJ, Lamberts SW, de Herder WW, et al. Medical therapy of acromegaly: efficacy and safety of somatostatin analogues. Drugs. (2009) 69:2207–26. doi: 10.2165/11318510-000000000-00000
13. Papaioannou C and Druce M. Preoperative medical treatments and surgical approaches for acromegaly: A systematic review. Clin Endocrinol (Oxf). (2023) 98:14–31. doi: 10.1111/cen.14790
14. Fleseriu M, Gurnell M, McCormack A, Fukuoka H, Glezer A, Langlois F, et al. Pituitary incidentaloma: A pituitary society international consensus guideline statement. Nat Rev Endocrinol. (2025) 21:638–55. doi: 10.1038/s41574-025-01134-8
15. Esposito D, Boguszewski CL, Colao A, Fleseriu M, Gatto F, Jørgensen JOL, et al. Diabetes mellitus in patients with acromegaly: pathophysiology, clinical challenges and management. Nat Rev Endocrinol. (2024) 20:541–52. doi: 10.1038/s41574-024-00993-x
16. Rosendal C, Arlien-Søborg MC, Nielsen EH, Andersen MS, Feltoft CL, Kistorp C, et al. The changing landscape of acromegaly - an epidemiological perspective. Rev Endocr Metab Disord. (2024) 25:691–705. doi: 10.1007/s11154-024-09875-z
17. Barkan AL, Lloyd RV, Chandler WF, Hatfield MK, Gebarski SS, Kelch RP, et al. Preoperative treatment of acromegaly with long-acting somatostatin analog sms 201-995: shrinkage of invasive pituitary macroadenomas and improved surgical remission rate. J Clin Endocrinol Metab. (1988) 67:1040–8. doi: 10.1210/jcem-67-5-1040
18. Kaplan HC, Baker HL Jr., Houser OW, Laws ER Jr., Abboud CF, and Scheithauer BW. Ct of the sella turcica after transsphenoidal resection of pituitary adenomas. AJR Am J Roentgenol. (1985) 145:1131–40. doi: 10.2214/ajr.145.6.1131
19. Molitch ME, Elton RL, Blackwell RE, Caldwell B, Chang RJ, Jaffe R, et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab. (1985) 60:698–705. doi: 10.1210/jcem-60-4-698
20. Ershadinia N and Tritos NA. Diagnosis and treatment of acromegaly: an update. Mayo Clin Proc. (2022) 97:333–46. doi: 10.1016/j.mayocp.2021.11.007
21. Fleseriu M, Langlois F, Lim DST, Varlamov EV, and Melmed S. Acromegaly: pathogenesis, diagnosis, and management. Lancet Diabetes Endocrinol. (2022) 10:804–26. doi: 10.1016/s2213-8587(22)00244-3
22. Sherlock M, Woods C, and Sheppard MC. Medical therapy in acromegaly. Nat Rev Endocrinol. (2011) 7:291–300. doi: 10.1038/nrendo.2011.42
23. Peverelli E, Treppiedi D, Mangili F, Catalano R, Spada A, and Mantovani G. Drug resistance in pituitary tumours: from cell membrane to intracellular signalling. Nat Rev Endocrinol. (2021) 17:560–71. doi: 10.1038/s41574-021-00514-0
24. Cordelier P, Estève JP, Bousquet C, Delesque N, O'Carroll AM, Schally AV, et al. Characterization of the antiproliferative signal mediated by the somatostatin receptor subtype sst5. Proc Natl Acad Sci U.S.A. (1997) 94:9343–8. doi: 10.1073/pnas.94.17.9343
25. Ferrante E, Pellegrini C, Bondioni S, Peverelli E, Locatelli M, Gelmini P, et al. Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2. Endocr Relat Cancer. (2006) 13:955–62. doi: 10.1677/erc.1.01191
26. Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, and Melmed S. Central and peripheral actions of somatostatin on the growth hormone-igf-I axis. J Clin Invest. (2004) 114:349–56. doi: 10.1172/jci19933
27. Öberg K and Lamberts SW. Somatostatin analogues in acromegaly and gastroenteropancreatic neuroendocrine tumours: past, present and future. Endocr Relat Cancer. (2016) 23:R551–r66. doi: 10.1530/erc-16-0151
28. Gomes-Porras M, Cárdenas-Salas J, and Álvarez-Escolá C. Somatostatin analogs in clinical practice: A review. Int J Mol Sci. (2020) 21:1682. doi: 10.3390/ijms21051682
29. Samson SL. Pasireotide in acromegaly: an overview of current mechanistic and clinical data. Neuroendocrinology. (2015) 102:8–17. doi: 10.1159/000381460
30. Urbani C, Dassie F, Zampetti B, Mioni R, Maffei P, Cozzi R, et al. Real-life data of pasireotide lar in acromegaly: A long-term follow-up. J Endocrinol Invest. (2024) 47:1733–41. doi: 10.1007/s40618-023-02275-1
31. Bolanowski M, Kałużny M, Witek P, and Jawiarczyk-Przybyłowska A. Pasireotide-a Novel Somatostatin Receptor Ligand after 20 years of Use. Rev Endocr Metab Disord. (2022) 23:601–20. doi: 10.1007/s11154-022-09710-3
32. Gadelha M, Bex M, Colao A, Pedroza García EM, Poiana C, Jimenez-Sanchez M, et al. Evaluation of the efficacy and safety of switching to pasireotide in patients with acromegaly inadequately controlled with first-generation somatostatin analogs. Front Endocrinol (Lausanne). (2019) 10:931. doi: 10.3389/fendo.2019.00931
33. Chang JS, Tseng HM, and Chang TC. Serial follow-up of presurgical treatment using pasireotide long-acting release with or without octreotide long-acting release for naïve active acromegaly. J Formos Med Assoc. (2016) 115:475–80. doi: 10.1016/j.jfma.2016.02.003
34. Yamamoto R, Robert Shima K, Igawa H, Kaikoi Y, Sasagawa Y, Hayashi Y, et al. Impact of preoperative pasireotide therapy on invasive octreotide-resistant acromegaly. Endocr J. (2018) 65:1061–7. doi: 10.1507/endocrj.EJ17-0487
35. Buchfelder M, Weigel D, Droste M, Mann K, Saller B, Brübach K, et al. Pituitary tumor size in acromegaly during pegvisomant treatment: experience from mr re-evaluations of the german pegvisomant observational study. Eur J Endocrinol. (2009) 161:27–35. doi: 10.1530/eje-08-0910
36. Buhk JH, Jung S, Psychogios MN, Göricke S, Hartz S, Schulz-Heise S, et al. Tumor volume of growth hormone-secreting pituitary adenomas during treatment with pegvisomant: A prospective multicenter study. J Clin Endocrinol Metab. (2010) 95:552–8. doi: 10.1210/jc.2009-1239
37. Jimenez C, Burman P, Abs R, Clemmons DR, Drake WM, Hutson KR, et al. Follow-up of pituitary tumor volume in patients with acromegaly treated with pegvisomant in clinical trials. Eur J Endocrinol. (2008) 159:517–23. doi: 10.1530/eje-08-0205
38. Schreiber I, Buchfelder M, Droste M, Forssmann K, Mann K, Saller B, et al. Treatment of acromegaly with the gh receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the german pegvisomant observational study. Eur J Endocrinol. (2007) 156:75–82. doi: 10.1530/eje.1.02312
39. Feola T, Cozzolino A, Simonelli I, Sbardella E, Pozza C, Giannetta E, et al. Pegvisomant improves glucose metabolism in acromegaly: A meta-analysis of prospective interventional studies. J Clin Endocrinol Metab. (2019) 104:2892–902. doi: 10.1210/jc.2018-02281
40. Fleseriu M, Führer-Sakel D, van der Lely AJ, De Marinis L, Brue T, van der Lans-Bussemaker J, et al. More than a decade of real-world experience of pegvisomant for acromegaly: acrostudy. Eur J Endocrinol. (2021) 185:525–38. doi: 10.1530/eje-21-0239
41. Parolin M, Dassie F, Alessio L, Wennberg A, Rossato M, Vettor R, et al. Obstructive sleep apnea in acromegaly and the effect of treatment: A systematic review and meta-analysis. J Clin Endocrinol Metab. (2020) 105:dgz116. doi: 10.1210/clinem/dgz116
42. Auriemma RS, Pivonello R, De Martino MC, Cudemo G, Grasso LF, Galdiero M, et al. Treatment with gh receptor antagonist in acromegaly: effect on cardiac arrhythmias. Eur J Endocrinol. (2013) 168:15–22. doi: 10.1530/eje-12-0596
43. Varlamov EV, McCartney S, and Fleseriu M. Functioning pituitary adenomas - current treatment options and emerging medical therapies. Eur Endocrinol. (2019) 15:30–40. doi: 10.17925/ee.2019.15.1.30
44. Lüdecke DK, Crock PA, Bidlingmaier M, and Schuppert F. Novel use of endogenous gh-measurement directly after transsphenoidal microsurgery in acromegaly treated with pegvisomant. Exp Clin Endocrinol Diabetes. (2013) 121:509–12. doi: 10.1055/s-0033-1347253
45. Stefaneanu L, Kovacs K, Horvath E, Buchfelder M, Fahlbusch R, and Lancranjan L. Dopamine D2 receptor gene expression in human adenohypophysial adenomas. Endocrine. (2001) 14:329–36. doi: 10.1385/endo:14:3:329
46. Moyes VJ, Metcalfe KA, and Drake WM. Clinical use of cabergoline as primary and adjunctive treatment for acromegaly. Eur J Endocrinol. (2008) 159:541–5. doi: 10.1530/eje-08-0306
47. Freda PU, Reyes CM, Nuruzzaman AT, Sundeen RE, Khandji AG, and Post KD. Cabergoline therapy of growth hormone & Growth hormone/prolactin secreting pituitary tumors. Pituitary. (2004) 7:21–30. doi: 10.1023/b:pitu.0000044630.83354.f0
48. Shen M, Shou X, Wang Y, Zhang Z, Wu J, Mao Y, et al. Effect of presurgical long-acting octreotide treatment in acromegaly patients with invasive pituitary macroadenomas: A prospective randomized study. Endocr J. (2010) 57:1035–44. doi: 10.1507/endocrj.k10e-203
49. Abe T and Lüdecke DK. Effects of preoperative octreotide treatment on different subtypes of 90 gh-secreting pituitary adenomas and outcome in one surgical centre. Eur J Endocrinol. (2001) 145:137–45. doi: 10.1530/eje.0.1450137
50. Oshino S, Saitoh Y, Kasayama S, Arita N, Ohnishi T, Kohara H, et al. Short-term preoperative octreotide treatment of gh-secreting pituitary adenoma: predictors of tumor shrinkage. Endocr J. (2006) 53:125–32. doi: 10.1507/endocrj.53.125
51. Mao ZG, Zhu YH, Tang HL, Wang DY, Zhou J, He DS, et al. Preoperative lanreotide treatment in acromegalic patients with macroadenomas increases short-term postoperative cure rates: A prospective, randomised trial. Eur J Endocrinol. (2010) 162:661–6. doi: 10.1530/eje-09-0908
52. Plöckinger U and Quabbe HJ. Presurgical octreotide treatment in acromegaly: no improvement of final growth hormone (Gh) concentration and pituitary function. A long-term case-control study. Acta Neurochir (Wien). (2005) 147:485–93. doi: 10.1007/s00701-005-0511-9
53. Carlsen SM, Svartberg J, Schreiner T, Aanderud S, Johannesen O, Skeie S, et al. Six-month preoperative octreotide treatment in unselected, de novo patients with acromegaly: effect on biochemistry, tumour volume, and postoperative cure. Clin Endocrinol (Oxf). (2011) 74:736–43. doi: 10.1111/j.1365-2265.2011.03982.x
54. Colao A, Auriemma RS, and Pivonello R. The effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly. Pituitary. (2016) 19:210–21. doi: 10.1007/s11102-015-0677-y
55. Melmed S, Bronstein MD, Chanson P, Klibanski A, Casanueva FF, Wass JAH, et al. A consensus statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. (2018) 14:552–61. doi: 10.1038/s41574-018-0058-5
56. Losa M, Garbin E, Pedone E, and Mortini P. Normal insulin-like growth factor 1 during somatostatin receptor ligand treatment predicts surgical cure in acromegaly. J Clin Endocrinol Metab. (2020) 105:dgaa424. doi: 10.1210/clinem/dgaa424
57. Colao A, Ferone D, Cappabianca P, del Basso De Caro ML, Marzullo P, Monticelli A, et al. Effect of octreotide pretreatment on surgical outcome in acromegaly. J Clin Endocrinol Metab. (1997) 82:3308–14. doi: 10.1210/jcem.82.10.4283
58. Carlsen SM, Lund-Johansen M, Schreiner T, Aanderud S, Johannesen O, Svartberg J, et al. Preoperative octreotide treatment in newly diagnosed acromegalic patients with macroadenomas increases cure short-term postoperative rates: A prospective, randomized trial. J Clin Endocrinol Metab. (2008) 93:2984–90. doi: 10.1210/jc.2008-0315
59. Losa M, Mortini P, Urbaz L, Ribotto P, Castrignanó T, and Giovanelli M. Presurgical treatment with somatostatin analogs in patients with acromegaly: effects on the remission and complication rates. J Neurosurg. (2006) 104:899–906. doi: 10.3171/jns.2006.104.6.899
60. Li ZQ, Quan Z, Tian HL, and Cheng M. Preoperative lanreotide treatment improves outcome in patients with acromegaly resulting from invasive pituitary macroadenoma. J Int Med Res. (2012) 40:517–24. doi: 10.1177/147323001204000213
61. Araujo-Castro M, Pian H, Ruz-Caracuel I, Acitores Cancela A, Pascual-Corrales E, and Rodríguez Berrocal V. Presurgical somatostatin receptor ligand treatment does not affect tumor consistency in gh-secreting pituitary macroadenomas. Endocr Connect. (2021) 10:102–9. doi: 10.1530/ec-20-0414
62. Lucas T, Astorga R, and Catalá M. Preoperative lanreotide treatment for gh-secreting pituitary adenomas: effect on tumour volume and predictive factors of significant tumour shrinkage. Clin Endocrinol (Oxf). (2003) 58:471–81. doi: 10.1046/j.1365-2265.2003.01741.x
63. Wasko R, Jankowska A, Kotwicka M, Liebert W, Sowinski J, and Warchol JB. Effects of treatment with somatostatin analogues on the occurrence of apoptosis in somatotropinomas. Neuro Endocrinol Lett. (2003) 24:334–8.
64. Saitoh Y, Arita N, Ohnishi T, Ekramullah S, Takemura K, and Hayakawa T. Absence of apoptosis in somatotropinomas treated with octreotide. Acta Neurochir (Wien). (1997) 139:851–6. doi: 10.1007/bf01411403
65. Losa M, Ciccarelli E, Mortini P, Barzaghi R, Gaia D, Faccani G, et al. Effects of octreotide treatment on the proliferation and apoptotic index of gh-secreting pituitary adenomas. J Clin Endocrinol Metab. (2001) 86:5194–200. doi: 10.1210/jcem.86.11.7986
66. Dagistanli FK, Ozkaya HM, Kucukyoruk B, Biceroglu H, Metin D, Gazioglu N, et al. Preoperative somatostatin analogue treatment might trigger apoptosis and autophagy in tumor tissues of patients with acromegaly: A pilot study. Exp Clin Endocrinol Diabetes. (2018) 126:168–75. doi: 10.1055/s-0042-107243
67. Lekva T, Berg JP, Heck A, Lyngvi Fougner S, Olstad OK, Ringstad G, et al. Attenuated rorc expression in the presence of emt progression in somatotroph adenomas following treatment with somatostatin analogs is associated with poor clinical recovery. PloS One. (2013) 8:e66927. doi: 10.1371/journal.pone.0066927
68. Fougner SL, Lekva T, Borota OC, Hald JK, Bollerslev J, and Berg JP. The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response. J Clin Endocrinol Metab. (2010) 95:2334–42. doi: 10.1210/jc.2009-2197
69. Venegas-Moreno E, Flores-Martinez A, Dios E, Vazquez-Borrego MC, Ibañez-Costa A, Madrazo-Atutxa A, et al. E-cadherin expression is associated with somatostatin analogue response in acromegaly. J Cell Mol Med. (2019) 23:3088–96. doi: 10.1111/jcmm.13851
70. Zhou K, Jin H, and Luo Y. Expression and significance of E-cadherin and B-catenins in pituitary adenoma. Int J Surg Pathol. (2013) 21:363–7. doi: 10.1177/1066896912471850
71. Gil J, Jordà M, Soldevila B, and Puig-Domingo M. Epithelial-mesenchymal transition in the resistance to somatostatin receptor ligands in acromegaly. Front Endocrinol (Lausanne). (2021) 12:646210. doi: 10.3389/fendo.2021.646210
72. Gil J, Marques-Pamies M, Valassi E, García-Martínez A, Serra G, Hostalot C, et al. Implications of heterogeneity of epithelial-mesenchymal states in acromegaly therapeutic pharmacologic response. Biomedicines. (2022) 10:460. doi: 10.3390/biomedicines10020460
73. Caron PJ, Bevan JS, Petersenn S, Flanagan D, Tabarin A, Prévost G, et al. Tumor shrinkage with lanreotide autogel 120 mg as primary therapy in acromegaly: results of a prospective multicenter clinical trial. J Clin Endocrinol Metab. (2014) 99:1282–90. doi: 10.1210/jc.2013-3318
74. Biermasz NR, van Dulken H, and Roelfsema F. Direct postoperative and follow-up results of transsphenoidal surgery in 19 acromegalic patients pretreated with octreotide compared to those in untreated matched controls. J Clin Endocrinol Metab. (1999) 84:3551–5. doi: 10.1210/jcem.84.10.6027
75. Fougner SL, Bollerslev J, Svartberg J, Øksnes M, Cooper J, and Carlsen SM. Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial. Eur J Endocrinol. (2014) 171:229–35. doi: 10.1530/eje-14-0249
76. Losa M, Donofrio CA, Gemma M, Barzaghi LR, and Mortini P. Pretreatment with somatostatin analogs does not affect the anesthesiologic management of patients with acromegaly. Pituitary. (2019) 22:187–94. doi: 10.1007/s11102-019-00952-0
77. Kristof RA, Stoffel-Wagner B, Klingmüller D, and Schramm J. Does octreotide treatment improve the surgical results of macro-adenomas in acromegaly? A randomized study. Acta Neurochir (Wien). (1999) 141:399–405. doi: 10.1007/s007010050316
78. Duan L, Zhu H, Xing B, and Gu F. Prolonged preoperative treatment of acromegaly with somatostatin analogs may improve surgical outcome in patients with invasive pituitary macroadenoma (Knosp grades 1-3): A retrospective cohort study conducted at a single center. BMC Endocr Disord. (2017) 17:55. doi: 10.1186/s12902-017-0205-3
79. Yao S, Chen WL, Tavakol S, Akter F, Catalino MP, Guo X, et al. Predictors of postoperative biochemical remission in acromegaly. J Neurooncol. (2021) 151:313–24. doi: 10.1007/s11060-020-03669-4
80. Pita-Gutierrez F, Pertega-Diaz S, Pita-Fernandez S, Pena L, Lugo G, Sangiao-Alvarellos S, et al. Place of preoperative treatment of acromegaly with somatostatin analog on surgical outcome: A systematic review and meta-analysis. PloS One. (2013) 8:e61523. doi: 10.1371/journal.pone.0061523
81. Beckers A. Does preoperative somatostatin analog treatment improve surgical cure rates in acromegaly? A new look at an old question. J Clin Endocrinol Metab. (2008) 93:2975–7. doi: 10.1210/jc.2008-1351
82. Yang C, Li G, Jiang S, Bao X, and Wang R. Preoperative somatostatin analogues in patients with newly-diagnosed acromegaly: A systematic review and meta-analysis of comparative studies. Sci Rep. (2019) 9:14070. doi: 10.1038/s41598-019-50639-6
83. Albarel F, Castinetti F, Morange I, Guibert N, Graillon T, Dufour H, et al. Pre-surgical medical treatment, a major prognostic factor for long-term remission in acromegaly. Pituitary. (2018) 21:615–23. doi: 10.1007/s11102-018-0916-0
84. Zhang S, Chen J, Yao S, Akter F, Wang Z, Hu B, et al. Predictors of postoperative biochemical remission in lower knosp grade growth hormone-secreting pituitary adenomas: A large single center study. J Endocrinol Invest. (2023) 46:465–76. doi: 10.1007/s40618-022-01873-9
85. Bolanowski M, Zgliczyński W, Sowiński J, Bałdys-Waligórska A, Bednarek-Tupikowska G, Witek P, et al. Therapeutic effect of presurgical treatment with longacting octreotide (Sandostatin® Lar®) in patients with acromegaly. Endokrynol Pol. (2020) 71:285–91. doi: 10.5603/EP.a2020.0050
86. Shen M, Yang Y, He W, Qiao N, He M, Shou X, et al. Efficacy and predictors of short-term first-generation somatostatin analog presurgical treatment in acromegaly: A hospital-based study of 237 cases. Growth Horm IGF Res. (2020) 55:101354. doi: 10.1016/j.ghir.2020.101354
87. Margusino-Framiñán L, Pertega-Diaz S, Pena-Bello L, Sangiao-Alvarellos S, Outeiriño-Blanco E, Pita-Gutierrez F, et al. Cost-effectiveness analysis of preoperative treatment of acromegaly with somatostatin analogue on surgical outcome. Eur J Intern Med. (2015) 26:736–41. doi: 10.1016/j.ejim.2015.07.019
88. Duan L, Huang M, Yan H, Zhang Y, and Gu F. Cost-effectiveness analysis of two therapeutic schemes in the treatment of acromegaly: A retrospective study of 168 cases. J Endocrinol Invest. (2015) 38:717–23. doi: 10.1007/s40618-015-0242-6
89. Hua YX, Deng Y, Liu M, Zang SJ, and Hu CY. Long-term cost-effectiveness of biphasic human insulin 30 in people with type 2 diabetes with inadequate glycaemic control on oral antidiabetic drugs in China. Value Health. (2014) 17:A745. doi: 10.1016/j.jval.2014.08.162
90. Sesmilo G, Gaztambide S, Venegas E, Picó A, Del Pozo C, Blanco C, et al. Changes in acromegaly treatment over four decades in Spain: analysis of the spanish acromegaly registry (Rea). Pituitary. (2013) 16:115–21. doi: 10.1007/s11102-012-0384-x
91. Bourdelot A, Coste J, Hazebroucq V, Gaillard S, Cazabat L, Bertagna X, et al. Clinical, hormonal and magnetic resonance imaging (Mri) predictors of transsphenoidal surgery outcome in acromegaly. Eur J Endocrinol. (2004) 150:763–71. doi: 10.1530/eje.0.1500763
92. Taghvaei M, Sadrehosseini SM, Ardakani JB, Nakhjavani M, and Zeinalizadeh M. Endoscopic endonasal approach to the growth hormone-secreting pituitary adenomas: endocrinologic outcome in 68 patients. World Neurosurg. (2018) 117:e259–e68. doi: 10.1016/j.wneu.2018.06.009
93. Diri H, Ozaslan E, Kurtsoy A, and Bayram F. A single-center observational study assessing the predictive factors associated with the prognosis of acromegaly. Growth Horm IGF Res. (2020) 55:101342. doi: 10.1016/j.ghir.2020.101342
94. Yan X, Chen X, Ge H, Zhu S, Lin Y, Kang D, et al. The change in distance between bilateral internal carotid arteries in acromegaly and its risk factors. Front Endocrinol (Lausanne). (2020) 11:429. doi: 10.3389/fendo.2020.00429
95. Wang YY, Higham C, Kearney T, Davis JR, Trainer P, and Gnanalingham KK. Acromegaly surgery in manchester revisited–the impact of reducing surgeon numbers and the 2010 consensus guidelines for disease remission. Clin Endocrinol (Oxf). (2012) 76:399–406. doi: 10.1111/j.1365-2265.2011.04193.x
96. Schöfl C, Franz H, Grussendorf M, Honegger J, Jaursch-Hancke C, Mayr B, et al. Long-term outcome in patients with acromegaly: analysis of 1344 patients from the german acromegaly register. Eur J Endocrinol. (2013) 168:39–47. doi: 10.1530/eje-12-0602
97. Ku CR, Kim EH, Oh MC, Lee EJ, and Kim SH. Surgical and endocrinological outcomes in the treatment of growth hormone-secreting pituitary adenomas according to the shift of surgical paradigm. Neurosurgery. (2012) 71:ons192–203. doi: 10.1227/NEU.0b013e318265a288
98. Gadelha MR, Wildemberg LE, Bronstein MD, Gatto F, and Ferone D. Somatostatin receptor ligands in the treatment of acromegaly. Pituitary. (2017) 20:100–8. doi: 10.1007/s11102-017-0791-0
99. Colao A, Auriemma RS, Lombardi G, and Pivonello R. Resistance to somatostatin analogs in acromegaly. Endocr Rev. (2011) 32:247–71. doi: 10.1210/er.2010-0002
100. Brzana J, Yedinak CG, Gultekin SH, Delashaw JB, and Fleseriu M. Growth hormone granulation pattern and somatostatin receptor subtype 2a correlate with postoperative somatostatin receptor ligand response in acromegaly: A large single center experience. Pituitary. (2013) 16:490–8. doi: 10.1007/s11102-012-0445-1
101. Gadelha MR, Kasuki L, and Korbonits M. Novel pathway for somatostatin analogs in patients with acromegaly. Trends Endocrinol Metab. (2013) 24:238–46. doi: 10.1016/j.tem.2012.11.007
102. Coopmans EC, Korevaar TIM, van Meyel SWF, Daly AF, Chanson P, Brue T, et al. Multivariable prediction model for biochemical response to first-generation somatostatin receptor ligands in acromegaly. J Clin Endocrinol Metab. (2020) 105:dgaa387. doi: 10.1210/clinem/dgaa387
103. Petersenn S, Houchard A, Sert C, and Caron PJ. Predictive factors for responses to primary medical treatment with lanreotide autogel 120 mg in acromegaly: post hoc analyses from the primarys study. Pituitary. (2020) 23:171–81. doi: 10.1007/s11102-019-01020-3
104. Lv L, Hu Y, Zhou P, Zhang S, Yin S, Zhang N, et al. Presurgical treatment with somatostatin analogues in growth hormone-secreting pituitary adenomas: A long-term single-center experience. Clin Neurol Neurosurg. (2018) 167:24–30. doi: 10.1016/j.clineuro.2018.02.006
105. Briceno V, Zaidi HA, Doucette JA, Onomichi KB, Alreshidi A, Mekary RA, et al. Efficacy of transsphenoidal surgery in achieving biochemical cure of growth hormone-secreting pituitary adenomas among patients with cavernous sinus invasion: A systematic review and meta-analysis. Neurol Res. (2017) 39:387–98. doi: 10.1080/01616412.2017.1296653
106. Bonneville F, Rivière LD, Petersenn S, Bevan J, Houchard A, Sert C, et al. Mri T2 signal intensity and tumor response in patients with gh-secreting pituitary macroadenoma: primarys post-hoc analysis. Eur J Endocrinol. (2018) 1:EJE-18-0254.R2. doi: 10.1530/eje-18-0254
107. Potorac I, Petrossians P, Daly AF, Alexopoulou O, Borot S, Sahnoun-Fathallah M, et al. T2-weighted mri signal predicts hormone and tumor responses to somatostatin analogs in acromegaly. Endocr Relat Cancer. (2016) 23:871–81. doi: 10.1530/erc-16-0356
108. Heck A, Emblem KE, Casar-Borota O, Bollerslev J, and Ringstad G. Quantitative analyses of T2-weighted mri as a potential marker for response to somatostatin analogs in newly diagnosed acromegaly. Endocrine. (2016) 52:333–43. doi: 10.1007/s12020-015-0766-8
109. Swanson AA, Erickson D, Donegan DM, Jenkins SM, Van Gompel JJ, Atkinson JLD, et al. Clinical, biological, radiological, and pathological comparison of sparsely and densely granulated somatotroph adenomas: A single center experience from a cohort of 131 patients with acromegaly. Pituitary. (2021) 24:192–206. doi: 10.1007/s11102-020-01096-2
110. Park YW, Kang Y, Ahn SS, Ku CR, Kim EH, Kim SH, et al. Radiomics model predicts granulation pattern in growth hormone-secreting pituitary adenomas. Pituitary. (2020) 23:691–700. doi: 10.1007/s11102-020-01077-5
111. Kocak B, Durmaz ES, Kadioglu P, Polat Korkmaz O, Comunoglu N, Tanriover N, et al. Predicting response to somatostatin analogues in acromegaly: machine learning-based high-dimensional quantitative texture analysis on T2-weighted mri. Eur Radiol. (2019) 29:2731–9. doi: 10.1007/s00330-018-5876-2
112. Park C, Yang I, Woo J, Kim S, Kim J, Kim Y, et al. Somatostatin (Srif) receptor subtype 2 and 5 gene expression in growth hormone-secreting pituitary adenomas: the relationship with endogenous srif activity and response to octreotide. Endocr J. (2004) 51:227–36. doi: 10.1507/endocrj.51.227
113. Plöckinger U, Bäder M, Hopfenmüller W, Saeger W, and Quabbe HJ. Results of somatostatin receptor scintigraphy do not predict pituitary tumor volume- and hormone-response to ocreotide therapy and do not correlate with tumor histology. Eur J Endocrinol. (1997) 136:369–76. doi: 10.1530/eje.0.1360369
114. Razzore P, Colao A, Baldelli R, Gaia D, Marzullo P, Ferretti E, et al. Comparison of six months therapy with octreotide versus lanreotide in acromegalic patients: A retrospective study. Clin Endocrinol (Oxf). (1999) 51:159–64. doi: 10.1046/j.1365-2265.1999.00812.x
115. Casar-Borota O, Heck A, Schulz S, Nesland JM, Ramm-Pettersen J, Lekva T, et al. Expression of sstr2a, but not of sstrs 1, 3, or 5 in somatotroph adenomas assessed by monoclonal antibodies was reduced by octreotide and correlated with the acute and long-term effects of octreotide. J Clin Endocrinol Metab. (2013) 98:E1730–9. doi: 10.1210/jc.2013-2145
116. Nunes VS, Correa JM, Puga ME, Silva EM, and Boguszewski CL. Preoperative somatostatin analogues versus direct transsphenoidal surgery for newly-diagnosed acromegaly patients: A systematic review and meta-analysis using the grade system. Pituitary. (2015) 18:500–8. doi: 10.1007/s11102-014-0602-9
117. Zhang L, Wu X, Yan Y, Qian J, Lu Y, and Luo C. Preoperative somatostatin analogs treatment in acromegalic patients with macroadenomas. A meta-analysis. Brain Dev. (2015) 37:181–90. doi: 10.1016/j.braindev.2014.04.009
118. Coelho MCA, Vasquez ML, Wildemberg LE, Vázquez-Borrego MC, Bitana L, Camacho A, et al. Molecular evidence and clinical importance of B-arrestins expression in patients with acromegaly. J Cell Mol Med. (2018) 22:2110–6. doi: 10.1111/jcmm.13427
119. Kasuki L, Vieira Neto L, Wildemberg LE, Colli LM, de Castro M, Takiya CM, et al. Aip expression in sporadic somatotropinomas is a predictor of the response to octreotide lar therapy independent of sstr2 expression. Endocr Relat Cancer. (2012) 19:L25–9. doi: 10.1530/erc-12-0020
120. Herkenhoff CGB, Trarbach EB, Batista RL, Soares IC, Frassetto FP, do Nascimento FBP, et al. Survivin: A potential marker of resistance to somatostatin receptor ligands. J Clin Endocrinol Metab. (2023) 108:876–87. doi: 10.1210/clinem/dgac610
121. Labadzhyan A, Nachtigall LB, Fleseriu M, Gordon MB, Molitch M, Kennedy L, et al. Oral octreotide capsules for the treatment of acromegaly: comparison of 2 phase 3 trial results. Pituitary. (2021) 24:943–53. doi: 10.1007/s11102-021-01163-2
Keywords: acromegaly, growth hormone, preoperative medical therapy, somatostatin analogs, molecular biomarkers
Citation: He D, Wang Q, Sheng Z and Li G (2026) Preoperative medical therapy for acromegaly: current knowledge and clinical significance. Front. Endocrinol. 16:1636047. doi: 10.3389/fendo.2025.1636047
Received: 27 May 2025; Accepted: 04 December 2025; Revised: 08 November 2025;
Published: 02 January 2026.
Edited by:
Hermann Lothar Mueller, Klinikum Oldenburg, GermanyReviewed by:
William Rojas, Hospital de San José, ColombiaClaudia Campana, University of Genoa, Italy
Copyright © 2026 He, Wang, Sheng and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhifeng Sheng, c2hlbmd6aGlmZW5nQGNzdS5lZHUuY24=; Guohua Li, Z2hsMzAxM0AxMjYuY29t