Pituitary growth hormone adenomas are slowly progressive diseases, but they can often cause multi-organ functional impairment. In adults it manifests mainly as acromegaly, with a total population incidence of about 70/1 million and about 2/1 million new cases per year [1]. The main clinical symptoms are fatigue, joint pain, headache, sensory abnormalities, and excessive sweating. The risk of death in patients with active acromegaly is two to four times higher than in the general population and is mainly related to the overproduction of circulating growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Therefore, clinical treatment focuses on normalizing GH and IGF-1 levels as soon as possible [2]. 1 Surgical treatment 1.1 Treatment overview Transsphenoidal microsurgery has been used to treat acromegaly for more than 40 years, and nowadays a less invasive direct transnasal approach is used. The remission rate is about 59%-95% in microadenomas, 26%-68% in macroadenomas, and 34%-74% overall. Transfrontal surgery is indicated for patients with tumor extension to the suprasellar or parasellar area, but its postoperative results are poor and complication rates are high; transfrontal surgery accounts for less than 5% of total surgical procedures, and remission rates for invasive tumors are significantly lower than those for microadenomas [3]. In untreated patients with persistent GH overproduction, GH levels also changed significantly, from (115 ± 127) mU/L preoperatively to (26 ± 33) mU/L postoperatively, p < 0.001; reflecting a largely resected tumor [2]. Postoperative recurrence rates have been reported to vary, ranging from 0 to 10%, with significantly reduced reoperative outcomes and postoperative remission rates even below 10% [4]. 1.2 Prognostic assessment Patients with acromegaly require long-term follow-up after surgery in order to accurately assess the long-term postoperative outcome and morbidity and mortality, but the literature reports that postoperative follow-up rarely reaches more than 10 years [5]. Reports over the last 30 years have shown that the postoperative mortality rate in patients with acromegaly is 1.01 to 3.3 times higher than that of the normal population [2], and that transsphenoidal surgery with appropriate adjuvant therapy can reduce the excess risk of death in patients with acromegaly to a level close to that of the normal population [5-6]. GH causes chronic complications such as diabetes mellitus, hypertension, hyperlipidemia and cardiovascular disease in patients with active acromegaly through direct or indirect effects, shortening life expectancy by approximately 10 years on average, with reversible morbidity and mortality when GH overproduction is controlled [2]. Arita et al [6] found the most significant decrease in the incidence of diabetes mellitus after surgery (from 33.8% to 14.3%, P < 0.05), while the incidence in untreated patients was about 10% to 50% [6]. In fact, any treatment modality can mostly reduce blood glucose levels to normal, but abnormal glucose tolerance is difficult to correct completely. The incidence of abnormal glucose tolerance in patients in remission with a minimum GH level (GH/OGTT) <0.4 ng/ml after glucose administration is still certain, and a clinical finding of 0.25 ng/ml is the more acceptable standard* [7]. Cardiovascular disease is the primary factor for excess mortality risk in patients with acromegaly, while abnormal glucose tolerance and hypertension further increase its incidence. Postoperative improvement in insulin sensitivity, glucose tolerance, and blood pressure, accompanied by normal GH/IGF-1 levels, will effectively reduce the risk of cardiovascular disease in patients [8]. Beauregard et al [5] treated 47 patients who remained in disease persistence after surgery with reoperation, drugs (octreotide), radiotherapy, or a combination, and still 13 died, with a 4.8-fold higher mortality rate than in the general population (P = 0.008). In patients in postoperative remission, survival was higher in the postoperative GH <2.5 ng/ml group than in the GH <5 ng/ml group, but was not statistically significant. Preoperative disease duration and short-term postoperative GH/OGTT minimum concentrations were good predictors of survival, and of the various indicators assessed for postoperative remission (GH, GH/OGTT, IGF-1), IGF-1 was the only factor significantly associated with survival, with the relative risk increasing to 4.78 in the group with elevated IGF-1. secretion with minimal fluctuations, and for some postoperative patients in clinical remission rather than complete cure, an annual measurement of IGF-1 levels is necessary for early detection of clinical relapse [2, 6]. 1.3 Prognostic implications Surgical treatment has the advantages of high cure rate, low morbidity and mortality, and low recurrence rate, and can restore GH to acceptable standards in a short time, but in some large adenomas, especially aggressive tumors with high secretory activity, surgery alone is still insufficient [4]. In high-grade tumors (grades III-IV), preoperative GH levels (>20 ng/ml) are an important predictor of persistent postoperative disease status, with no statistically significant effect of age and gender on postoperative outcomes [5]. Many studies have found that postoperative remission rates are further improved when surgery is performed in an experienced center, especially with the synergistic treatment of experienced operators and endocrinologists [9]. Tumor immunostaining also has the potential to influence postoperative remission rates, as De et al [4] found higher postoperative remission rates in single GH-positive patients than in patients with mixed GH and PRL tumors. Other complications include anterior pituitary insufficiency (incidence varies), cerebrospinal fluid nasal leakage (1.7%-7%), and meningitis (about 3%), etc. The incidence of complications is highly correlated with the proportion of macroadenomas and operator experience [2, 4]. The rate of complications is highly correlated with the proportion of macroadenomas and operator experience [2, 4]. Disorders of plasma osmolality and fluid balance are the most common, including central dysuria and the syndrome of inappropriate antidiuretic hormone (SIADH), and more than half of patients may experience transient polyuria or hyponatremia [10]. Blood sodium levels usually reach their lowest point around 7 d postoperatively. Delayed hyponatremia is defined as a serum sodium level below 135 mmol/L 3 or more d postoperatively, and the vast majority of patients present with asymptomatic hyponatremia, mainly caused by SIADH, with other causes including low cortisol levels, volume overload, and hypothyroidism. Asymptomatic patients are given a water- and salt-restricted diet, while those with symptoms (headache, nausea, vomiting or even lethargy) should be admitted to hospital and electrolyte levels monitored. In the literature, it has been reported that no patient developed hypernatremia or central pontine demyelination when additional 3% hypertonic sodium chloride was administered intravenously at 30-40 ml/h for an average of 33 h [10]. To prevent cerebrospinal fluid nasal leakage, transsphenoidal saddle reconstruction or repair is routinely performed after transsphenoidal surgery. It was concluded that a single saddle base reconstruction avoiding intersaddle filling is equally safe and effective, with no significant difference in the incidence of complications such as morbidity and mortality and empty saddle syndrome, while avoiding reoperation and reducing the risk of overfilling and postoperative interference with MRI review [11]. 2 Drug therapy 2.1 Overview Surgical cure rates for pituitary macroadenomas and invasive tumors are on a significant decline, and some patients with microadenomas who do not wish to undergo surgery, or who are at high surgical risk, may be treated successfully with growth inhibitor analogs alone as a long-term treatment strategy [12-13]. In addition, some patients who are concerned about postoperative hypogonadism or whose MRI does not clearly indicate the presence of adenomas can also be effectively treated with drugs [14]. 2.2 Treatment options Dopamine agonists, such as cartegolins and bromocriptine, can reduce GH levels by unknown mechanisms, but rarely reduce GH/IGF-1 to acceptable levels [15]. Octreotide is a synthetic long-acting growth inhibitor analogue, which is administered subcutaneously in three daily doses, and is now mainly used in its extended-release formulations octreotide (octreotide LAR, OCLAR) such as SandostatinTM LARTM and lanreotide SR (LAN SR) such as SomatulineTM and The starting dose of OCLAR is usually 20 mg intramuscularly for 28 d/dose, and the dose is adjusted to 30 mg or 10 mg for 28 d/dose depending on the initial efficacy if GH/IGF-1 is still in pathological secretion (IGF-1 decreases more than 50% of the upper limit of normal). lan SR is usually 30 mg intramuscularly for 7-10 d/dose. LAN Autogel 60-120 mg depending on GH levels, 1 month/dose [13]. The growth hormone receptor inhibitor Pegvisomant represents a new concept in the treatment of acromegaly and is currently the most effective drug for restoring circulating IGF-1 levels, mainly inhibiting GH activity rather than GH secretion.Pegvisomant is administered subcutaneously at a dose of 10-40 mg for 1 d/dose [15]. 2.3 Current status of treatment In recent years, it has been reported that the overall remission rate of drug therapy is 40%-57% and the normalization rate of IGF-1 is about 40%-97% [12, 15-16]. If OCLAR is used as the primary treatment modality, it can largely normalize GH/IGF-1 levels and significantly reduce adenoma volume, especially in those patients with large adenomas with high GH levels. Compared to OCLAR, LAN SR showed no significant difference in tumor size reduction and control of biochemical indicators such as GH/IGF-1 [13]. However, it is noteworthy that none of the patients with GH >50 mU/L before treatment were able to achieve all three criteria (GH <5 mU/L, normalization of IGF-1 and tumor volume reduction >30%), but more than half of them could be successfully treated [17]. GH and IGF-1 tend to decrease within 6 to 12 months after drug administration, with further decreases in IGF-1 levels after 6 months [12]. Twenty-four weeks after the end of treatment, 50% to 88% of patients had varying degrees of symptom disappearance, especially headache, excessive sweating and arthralgia (21%), sensory abnormalities (38%), fatigue (26.4%) and carpal tunnel syndrome (15%) [16]. 2.4 Prognostic implications Octreotide treatment has a bidirectional effect on glucose metabolism, resulting in an increase in fasting glucose in patients with normal blood glucose, with cholesterol unaffected and triglycerides appearing elevated during treatment [12].Pegvisomant reduces blood insulin and glucose levels by blocking GH signaling, while increasing insulin activity [15]. Tumor size is a major factor in surgical failure and postoperative pituitary hypofunction. Therefore, the rational use of preoperative pharmacotherapy may improve the prognosis of surgery to some extent, even in patients with visual field defects [12]. Preoperative drug therapy should not exceed 12 months, as the tumor size is no longer significantly reduced with continued drug use (P > 0.05). Postoperative treatment with growth inhibitor analogs resulted in significantly higher IGF-1 normalization rates and was largely free of pituitary impairment [13]. Although nearly half of the patients had drug side effects, they were well tolerated, with adverse effects mainly being gastrointestinal discomfort, cholelithiasis or cholestasis [16]. 3 Radiotherapy 3.1 Overview Radiosurgery for pituitary adenomas has a history of nearly half a century and mainly includes traditional external beam fractionated radiotherapy, modified linear gas pedal or heavy particle gas pedal radiotherapy and stereotactic 3D localization therapy, such as gamma knife and X-knife. Radiotherapy has long been less frequently reported as a first-line treatment option in pituitary growth hormone adenomas and has been used as an adjuvant. Currently, radiosurgery mainly selectively targets adenoma tissue with high doses of radiation while rarely affecting the surrounding normal tissue. Data suggest that gamma knife treatment of patients with acromegaly is more effective and safer than conventional radiation therapy in suppressing hormonal overproduction and controlling tumor volume [18]. 3.2 Current treatment status The rate of GH normalization (<2.5 ng/ml) after radiotherapy ranges from 37% to 85%, with slow improvement in clinical performance being the main feature, and hormone normalization is not even achieved until 10 years after treatment, thus increasing the difficulty of clinical studies [14, 18]. Likewise, for those who do not have significant efficacy after radiosurgery, no further surgery or radiotherapy should be performed within 5 years, during which time GH and IGF-1 are still in the process of normalization [19]. The effectiveness of Gamma Knife as the first or adjuvant treatment has been less reported, Castinetti et al [20] showed for the first time in a controlled study that there was no significant difference in the success rate of Gamma Knife as primary treatment or re-treatment after neurosurgery, and that there was no significant difference between Gamma Knife treatment combined with growth inhibitor agonists (20% of patients in remission) and Gamma Knife treatment alone (15% of patients in remission) There is no significant difference between gamma knife treatment combined with growth inhibitor agonists (20% of patients in remission) and gamma knife alone (15% of patients in remission). 3.3 Complications The most common side effects are impaired visual function (incidence 17%) and hypothalamic pituitary hypofunction (incidence 55%) [21]. The shortcoming of conventional radiation therapy is the high incidence of hypopituitarism, which can occur years after radiotherapy and varies widely in the literature depending on the follow-up time (incidence 16%-85%), and stereotactic targeted therapy (e.g., gamma knife) can reduce the incidence of hypopituitarism accordingly [14]. The rate of hormone normalization is positively correlated with the radiation dose to pituitary tissue, but the average radiation dose is an important cause of pituitary hypoplasia, so it is crucial to establish a maximum safe limit dose value. Experience from long-term follow-up suggests that the lowest possible dose should be chosen: 40-45 Gy for conventional treatment, 1.8 Gy for fractionated irradiation, 15-20 Gy for stereotactic treatment marginal dose averages, and less than 8 Gy depending on the cross* site, yet low dose irradiation still does not completely prevent the development of pituitary function impairment [3, 18, 21]. In conclusion, surgical treatment is still the treatment of choice for acromegaly, and further treatment with drugs is usually given to some untreated patients or those with poor outcomes. In some patients with aggressive tumors or large residual tumors that are intolerant to drug therapy, radiation therapy is an important option and should be clinically individualized. Meanwhile, economic factors are also a non-negligible problem, especially long-term drug therapy. Xue-Ming Lu, Department of Neurosurgery, General Hospital of Jinan Military Region