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).

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.

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.

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.

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).

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.

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).

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).

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).

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.

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.