Internal treatment of pituitary adenoma Pituitary adenoma is a common tumor of the nervous and endocrine system, and its detection rate has gradually increased with the improvement of diagnostic techniques. Treatment of pituitary tumors includes medications, surgery and radiation therapy. Generally, transsphenoidal surgery is the treatment of choice; however, surgery brings various complications and many large adenomas (>1 cm in diameter) recur within 5 years after surgery; and radiation therapy can cause irreversible pituitary hypoplasia. A number of medications are available: Bromocriptine, Pergolide, Quinagolide, and Cabergoline are the preferred dopamine agonists for PRL tumors.
1.1 Bromocriptine is an ergot derivative, and years of safe use suggest that it is the drug of choice for patients who need to restore ovulation. It normalizes PRL levels in 82% of female microadenoma patients and restores menstruation and ovulation in 90%. The recommended starting dose is 0.625 mg/d at bedtime, followed by 1.25 mg daily in the morning for one week, then 1.25 mg/d weekly for a total of 5.0 mg/d. Thereafter, PRL levels are reviewed monthly and the effective dose (restoration of menstruation and PRL levels) is usually 5.0-7.5 mg/d, with 7.5-10 mg/d for macroadenomas. To achieve optimal efficacy, bromocriptine should be taken twice daily. Treatment should be discontinued after 24 months or more, and 25% of patients may remain normal after discontinuation of the drug.
1.2 Cabergoline is a non-ergot derivative that binds more tightly to D2 receptors, has a longer duration of action, and has fewer side effects than bromocriptine. After 24 months of treatment (0.25mg×1 time in the first week, 0.25mg×2 times in the second week, and gradually adjusted according to the suppression level of PRL thereafter, the highest dose is 0.5mg/d) for male prolactinoma, PRL can be normalized in 75%-80% of patients, tumor diameter is reduced by 72%-73%, breast discharge disappears, and sex hormone, semen volume and sperm count are restored in most patients. The sex hormone, semen volume and sperm count of most patients were restored. After stopping the treatment of microadenoma with cabergoline 1mg/week for 48 months, the follow-up period was 2-5 years, and it was found that 30% of the patients reappeared with hyperprolactinemia around 12 months after stopping the drug, but there was no evidence of tumor recurrence. After 46 months of discontinuation of capsaicin 1 mg/week for macroadenoma, 36% of patients had reappearance of hyperprolactinemia around 18 months of discontinuation, but there was no evidence of tumor recurrence, and prolactin levels were still controlled in 64% of patients after 48 months of discontinuation. However, KaplanCMeier analysis suggested that the rate of tumor recurrence was significantly higher at 5 years of drug discontinuation compared to no tumor hyperprolactinemia.
2. GH tumors Growth inhibitory analogs, growth hormone receptor antagonists and dopamine agonists are commonly used drugs.
2.1 Growth hormone analogues were first used for the treatment of intestinal tumors and are now available for the treatment of growth hormone tumors and TSH tumors, commonly used drugs include octreotide and its long-acting preparations as well as Lanreotide, SOM230 and so on. The mechanism of action is to bind growth inhibitory receptor SSTR (mainly SSTR2 and SSTR5), inhibit intracellular adenylate cyclase, reduce cAMP production and thus inhibit GH secretion and cell proliferation. Clinical efficacy includes inhibition of GH and IGF-1 levels, improvement of headache and acromegaly symptoms, and reduction of tumor size. The main side effects of growth inhibitor analogs are gastrointestinal reactions and gallbladder stones, but they are relatively mild. The poor efficacy of growth inhibitor analogs (growth inhibitor resistance) may be due to SSTR mutations, and two C→T mutations have been found in the SSTR5 gene in the genome and tumor DNA that prevent growth inhibitors from acting properly.
2.1.1 Octreotide long-acting preparation (Octreotide LAR) has a longer duration of action of about 4 weeks, with 20 mg per intramuscular injection and a typical injection interval of 28 days, and after 6 months GH levels decreased from 27.6 ng/ml to 5.03 ± 5.38 ng/ml and IGF-1 decreased from 889.55 ± 167.29 ng/ml to 483.00 ± 239.71 ng/ml (n=9), and 66% of the patients had a reduction in tumor volume. Another group of 110 patients with acromegaly was treated with Octreotide LAR, 20 mg every 28 days for 3 injections, which was gradually adjusted over a mean period of 30 (18-54) months, with a final maintenance dose ranging from 10 to 40 mg/dose, mostly 20-30 mg/dose. GH levels decreased from 20.7 ± 2.4µg/L at baseline to 2.2 ± 0.2µg/L and IGF levels decreased from 770 ± 26µg/L to 276 ± 15 µg/L, where significant efficacy was already seen at 3 months of treatment. 2.1.2 The duration of action of lanreotide was slightly shorter, about 10 days. After an average of 24 months of treatment in 92 patients with acromegaly, GH in 88% of patients and IGF-1 in 65% of patients decreased to the normal range, and the proportion of patients with normalized IGF-1 gradually increased from 49% in the first year to 77% in the third year, and nearly half of patients had a reduction in tumor volume.
2.1.3 SOM230, a new growth inhibitor analogue with a half-life of 23 hours, was also found to significantly inhibit GH secretion (GH inhibition rate of 22%-68%) and reduce IGF-1 levels in in vitro tests. . The inhibition of GH/PRL tumor and lactin cells (mainly mediated by SSTR5) is stronger than that of octreotide.
2.2 Pegvisomant is the first GH receptor antagonist in clinical use (approved for marketing in the US and Europe in 2003, respectively), which blocks the formation of GH receptor dimers, thereby preventing the peripheral effects of GH. It can reduce IGF-1 levels to normal, significantly alleviate signs and symptoms, and correct metabolic disorders with mild side effects. However, since it acts in the periphery, it has no effect on tumor volume reduction. Therefore, GH should not be used as an efficacy measure after treatment, but IGF-1 should be used to evaluate. It is suitable for patients who are resistant or intolerant to growth inhibitor analogues. 16 patients with acromegaly were given Pegvisomant at a starting dose of 10 mg/d, which was increased by 5 mg/d every 8 weeks according to the efficacy, usually with a mean therapeutic dose of 20 (10-40) mg/d. All patients were followed up for 7 (3-11) months and IGF-1 decreased to within the age-appropriate normal range.
2.3 Dopamine agonists are generally used in pituitary tumors with high PRL secretion, but they also have a suppressive effect on GH secretion, so they are more effective in combination with growth inhibitory analogs. The efficacy of GH/PRL tumors on DA and SST analogs has been found to be inconsistent clinically and experimentally, and tumor uptake 111In-OCT and 123I-IBZM (indicators of dopamine agonist action) have been confirmed by nuclear scan to be inconsistent in various GH/PRL tumors, which may be the reason for the different efficacy.
3. ACTH tumors Because of the generally small size of the tumor and the high metabolic impact on the body, transsphenoidal surgery is preferred. However, drug therapy is also an alternative for patients who are unable to undergo surgery or whose surgery has failed. Traditional drugs such as methylphenidate and enlumide are limited in clinical application because of their large side effects. Since ACTH tumors expressing D2 receptors account for 70% to 80% of ACTH tumors, both in vitro experiments and clinical studies have found a significant decrease in ACTH secretion after intervention with the D2 agonist cabergoline for D2 receptor-positive ACTH tumors.
4. TSH tumors Surgery is the treatment of choice. If surgery is not possible, radiotherapy or drug therapy can be chosen. The former includes PTU or tabazol and beta blockers; the latter includes growth inhibitor analogs and dopamine agonists, especially growth inhibitor analogs can suppress TSH secretion in 90% of patients (down to less than 50% of baseline), and long-term follow-up can normalize thyroid function in 96% of patients and reduce tumor size in 45% of patients, with no effect on the fetus. In addition, postoperative central hypothyroidism is common, and attention should be paid to thyroid hormone supplementation.
5. Non-functional tumors Clinical pituitary tumors without endocrine manifestations are often accompanied by high secretion of LH, FSH and glycoprotein alpha subunits, while in 67% of tumors there is expression of D2 receptors, which are divided into two subtypes, long and short, according to the difference in gene selective shearing. Treatment with capsaicin for 1 year resulted in a significant decrease in these secretions and a reduction in tumor size in nearly 60% of patients, with the best efficacy for capsaicin being in tumors expressing the short D2 receptor subtype. It has also been found that growth inhibitory receptors are expressed on the surface of endocrine incompetent tumor cells, and octreotide inhibits gonadotropin and glycoprotein alpha subunit secretion both in vivo and in vitro. However, the actual clinical efficacy is not optimistic, only about 10% of cases have mild tumor volume reduction.
In vitro experiments have confirmed that PPARγ is only expressed in normal pituitary ACTH cells, but can be expressed in all pituitary tumor cells. The mechanism is to inhibit cell cycle, prevent quiescent cells from entering G0 to G1 phase, reduce the number of cells entering S phase, and reduce the secretion of hormones from tumor cells. It may become a new option for the treatment of pituitary tumors. In conclusion, patients with pituitary tumors are receiving more and more benefits as medical treatment continues to advance and the level of surgery and radiation therapy continues to improve. There are more and more treatment options available, and some drugs have become the first choice for the treatment of certain types of pituitary tumors. Therefore, it is more and more important to choose the most suitable treatment plan (surgery, drugs, radiotherapy and their interplay) for different patients.
A friendly reminder: only a few pituitary tumors can be treated or controlled medically in clinical practice, and many of the above drugs are still under research, so individualized treatment is needed.