1.Surgical treatment: Surgical removal of the tumor is the treatment of choice for patients with pituitary GH adenoma. Surgery is recommended as the first-line treatment option for patients with microadenomas, as well as for patients with focal growth of pituitary macroadenomas with potential surgical cure, because surgery can effectively control the tumor in the long term and normalize the associated biochemical indicators. Transsphenoidal sinus surgery to remove pituitary adenomas is safe and effective for patients with large limbs, with fewer complications and lower mortality than other surgical methods (e.g., craniotomy).
2.Pharmacological treatment: Pharmacological treatment for limbomegaly includes growth inhibitor receptor ligands (SRL), namely: SSA, dopamine receptor agonists (DA), GH receptor antagonists, which are mainly used as adjuvant therapy for patients with unremitting disease after surgery. Drug therapy may also be preferred for patients who are not suitable for surgery in patients with large adenomas that are not expected to be completely removed by surgery and do not have symptoms of tumor compression, including: patients with poor systemic conditions that make it difficult to tolerate the risks of surgery; patients with high risk of anesthesia due to airway problems; patients with severe systemic manifestations of large limbs such as cardiomyopathy, severe hypertension and uncontrolled diabetes mellitus, or patients who are unwilling to undergo surgery. Growth inhibitor analogs are the first choice in pharmacological treatment.
(1) SSA: Growth inhibitory hormone (SST) is processed by precursors into two biologically active forms, SST-14 and -28. Natural SST has a plasma half-life of less than 3 min, and synthetic growth inhibitory hormone analogs can mimic the physiological effects of SST and inhibit GH overproduction.
①SSA plays a role in the treatment of limb enlargement in 5 phases.
A. First-line treatment: for patients with large adenomas that are not expected to be completely resected by surgery and do not have symptoms of tumor compression, patients who are unwilling to undergo surgery, and patients who are not suitable for surgery, including: patients with poor systemic conditions that make it difficult to tolerate the risks of surgery; patients with high risk of anesthesia due to airway problems; and patients with severe systemic manifestations of limbomegaly (including cardiomyopathy, severe hypertension, and uncontrolled diabetes).
B. Pre-surgical treatment: For patients with serious complications and poor basic conditions, such as obvious respiratory dysfunction, cardiac insufficiency and patients with severe metabolic disorders, pre-surgical drug treatment can reduce serum GH and IGF-1 levels, and combined with related medical treatment can improve cardiopulmonary function to reduce the risk of anesthesia and surgery, as well as reduce tumor volume, so it is possible to improve the surgical outcome. As mentioned above, preoperative use of SSA can improve the postoperative remission rate in patients with macroadenoma.
C. Adjuvant therapy for residual tumor after tumor resection: If OGTT GH trough value <1.0 μg/L is the goal of cure, about 10% of patients with microadenoma and 55% of patients with macroadenoma need adjuvant therapy after surgery. Therefore, it is recommended that: patients with postoperative OGTT GH trough <1.0 μg/L and IGF-1 within normal range should be followed up regularly; patients with postoperative OGTT GH trough >1.0 μg/L, or elevated IGF-1, or still have significant symptoms of limb enlargement such as headache, should receive SSA therapy for at least 3-6 months, and depending on the changes in GH and IGF-1, decide whether to treat long-term or combined with radiation therapy.
D. Transitional treatment after radiotherapy: Since the serum GH and IGF-1 level decreases slowly after radiotherapy, SSA can be used for transitional treatment during the waiting period before radiotherapy takes full effect.
E. Treatment of complications: SSA treatment can improve the complications related to limb size such as hypertension, cardiac insufficiency and respiratory dysfunction.
② Efficacy of SSA.
A. Reduction of tumor volume: tumor growth was controlled in more than 97% of patients treated with SSA.
B. Control of serum GH and IGF-1 levels: SSA can normalize GH and IGF-1 levels in about 55% of patients, and the drug efficacy is negatively correlated with tumor volume and GH hypersecretion levels.
C. Improvement of clinical symptoms: SSA can reduce the tumor volume by effectively controlling GH and IGF-1, so as to comprehensively control the symptoms of limbomegaly, for example: SSA can significantly improve five common symptoms of limbomegaly: headache, fatigue, excessive sweating, joint pain and abnormal sensation.
D. Control of complications: As mentioned before SSA can bring obvious cardiovascular benefits and improve respiratory dysfunction, even left ventricular hypertrophy and sleep apnea syndrome will disappear after receiving SSA treatment.
③Adverse reactions of SSA: The adverse reactions of SSA are mainly injection site reactions and gastrointestinal symptoms, which are usually mild to moderate. 10% to 205 patients have local discomfort, erythema or swelling, pain and pruritus from injection. 5% to 155 patients have gastrointestinal symptoms, diarrhea, abdominal pain, bloating, steatorrhea, nausea and vomiting, but they are usually transient . Long-term use of SSA can increase the incidence of gallbladder sludge or gallstones, which are usually asymptomatic, not clinically significant, and generally do not require surgical intervention and can be detected by periodic ultrasound. Rare adverse effects also include alopecia, bradycardia, and constipation.
(2) Dopamine agonists: Dopamine agonists can inhibit GH release through dopamine receptors in the hypothalamus. The most commonly used dopamine agonists include ergot derivatives bromocriptine and carte blanche, whose biggest advantage is that they can be taken orally and are relatively inexpensive. 10% to 20% of patients with mild to moderately elevated GH levels have their GH and IGF-1 levels reduced to satisfactory levels after using these drugs at doses two to four times higher than those used to treat PRL tumors. Adverse effects of dopamine receptor agonists include gastrointestinal discomfort, upright hypotension, headache, nasal congestion and constipation. Currently, only the first generation dopamine receptor agonist bromocriptine is available in China. This drug is suitable for patients with mildly elevated GH levels who have failed to use SSA for other reasons.
(3) Drug combination therapy: The combination of drugs with different mechanisms of action may have a synergistic effect. In patients with partial response to SSA therapy, combination therapy with dopamine agonists may further reduce GH or IGF-1 levels.
3. Radiation and radiosurgery treatment.
(1) Status of radiotherapy: Considering the complications such as slow decrease of serum GH level and hypopituitarism, radiotherapy is usually not used as the first choice treatment option for pituitary GH adenoma, but is most often used as an adjuvant treatment for incomplete postoperative remission and residual and recurrent tumors. Patients with GH hypersecretion status after surgery may be treated with radiotherapy. Radiotherapy may also be the treatment of choice for patients who cannot undergo surgery.
(2) Radiosurgery: Traditional fractionated radiotherapy usually takes 6 months to 2 years to be effective, with some taking 5 to 15 years to be fully effective, and has been used in the past to control tumor growth and achieve biochemical remission. Recently, studies have looked at the effectiveness of high-dose targeted radiotherapy (single or multiple sessions) for residual pituitary tumor foci. These methods include stereotactic radiosurgery (gamma knife and x-ray knife) and proton beam therapy. Studies on outcomes and complications have shown that stereotactic radiotherapy and stereotactic radiosurgery (e.g., Gamma Knife) provide faster remission than conventional radiotherapy.
Some studies have shown that 40% of patients with normal GH levels at 12 months are treated, but not all patients are candidates for radiosurgery because of its effect on vision. In general, stereotactic radiosurgery is used for small to medium diameter residual or recurrent tumors and for patients who are intolerant of or refuse surgical treatment. The distance between the tumor and the optic cross or optic nerve should preferably be >2-5 mm to avoid visual impairment. Secondly radiosurgery requires special attention to the impact on fertility. The recurrence rate of large limb is 2% to 14%. Prophylactic radiotherapy is not recommended for patients who have undergone successful surgery and have normal serum GH levels. However, each patient should be routinely evaluated by follow-up every 6-12 months for at least 5 years to facilitate timely detection of any signs of recurrence and, if necessary, immediate treatment.
(3) Complications of radiotherapy and radiosurgery: The most common complication is impaired anterior pituitary function, which occurs in about 30% of cases and usually requires hormone replacement therapy. Long-term follow-up studies have shown a high incidence of impaired pituitary function with conventional radiotherapy. Other rare complications include visual impairment, radiation brain necrosis, and malignancy secondary to radiation field. The potential neuropsychiatric effects of radiotherapy and the incidence of secondary tumors, especially in patients with cerebrovascular disease and organic encephalopathy, need to be further investigated. The disadvantages of conventional radiotherapy also include the slow decline in GH levels.