The pathogenesis of pituitary adenomas has long been characterized by two different theories: (1) defects in the pituitary gland itself and (2) hypothalamic dysfunction. In the former case, the pituitary cells are hyperfunctional and form adenomas purely due to local factors, and early removal of microadenomas is expected to result in a cure. In the latter case, pituitary adenomas are formed due to hypothalamic dysfunction that triggers pituitary lesions. Therefore, pituitary adenomas are only a stage of endocrine dysfunction in the hypothalamus. Therefore, resection of pituitary adenomas can only treat the symptoms but not the root cause, and must be supplemented by hypothalamic radiotherapy or drug treatment after surgery, and is prone to recurrence. The clonal nature of pituitary tumors has been debated for a long time. Monoclonal tumors are caused by mutations in the nucleus of a single cell, resulting in the inactivation of an oncogene or a tumour suppressor gene (tumo r suppso rgene). Polyclonal tumors, on the other hand, result from exogenous stimuli (growth factors, hypothalamic prohormones, etc.) that lead to the proliferation of a group of cells. In recent years, the rapid progress of molecular biology, cell biology, genetics, immunology and other disciplines has contributed to the rapid development of endocrinology, new concepts continue to emerge, old concepts have been updated, and the pathogenesis of pituitary adenomas has been gradually clarified. The role of gene mutation in the development of pituitary adenomas Proto-oncogene mutation and pituitary adenomas: GsA gene mutation The G protein family is a group of guanosine triphosphate (GTP) binding proteins, which is an important link in the transmission of information from the receptor to the effector. More than 30 G proteins are known to form a superfamily. According to their relative molecular mass (M r), they are divided into two major groups. Large G proteins [M r (80-90) × 103 ] are heterotrimers composed of A, B, and C subunits, and are closely related to the transmission of hormone information. Small G proteins [M r (20-25) × 103 ] are only a polypeptide chain, equivalent to the A subunit of large G proteins, and are generally referred to as heterotrimeric large G proteins. G proteins can be divided into four groups according to the A subunit, Gs, Gi, Gq, and G12, of which excitatory G proteins (stimulant G proteins (stimulocyclic acid), GsA) are closely related to the effector of adenylylate cyclase (adenylate cyclase, ACA), which is coupled to the G proteins. The excitatory G protein (st im u lato ryGA, GsA) exerts an excitatory effect on its coupled effector adenylate cyclase (AC), whereas the inhibitory G protein (inh ib ito2ry GA, GiA) exerts an inhibitory effect on AC. The cDNAs of 21 A subunits, including GsA and GiA, have been cloned. G proteins are active when bound to GTP and inactivated when GTP is hydrolyzed to GDP. In some endocrine tumors, mutations in G proteins, where mutant gsA inhibits GTP hydrolysis, lead to persistent activation of the GsA subunit. For example, in about 40% of the tumor cells of pituitary growth hormone (GH) adenomas, mutations in the gsA gene are present at position 201 A rg, from CGT (A rg) to TGT (Cys) or CGT (A rg) to CA T (H is), followed by position 227 Glu, from Glu to A rg or Glu to Leu. rg is required for GTPase activity. Therefore, the mutation of A rg in position 201 of GsA will cause GsA to lose its GTPase activity, which will keep G protein in the activated state (GsAGTP), thus activating AC, increasing the cAM P content of tumor cells, and then causing tumor cells to secrete a large amount of GH through the cAM PöP KA pathway (the secretion of GH is cAM P-dependent), and promoting its cell proliferation. To date, although it is not certain whether mutations in gsA can cause pituitary adenomas, it has been indirectly shown in transgenic animal models that persistent activation of GsA may play an important role in the pathogenesis of pituitary adenomas. Although mutations in gsA play an important role in the pathogenesis of GH adenomas and its mutation rate is high, the incidence in pituitary PRL adenomas, ACTH adenomas, and TSH adenomas is very low. This may be due to the fact that the hypothalamic releasing hormone, which regulates the secretion of these hormones, acts through other types of G proteins rather than through GsA. For example, LHRH acts through the Gq11 protein, and TRH acts through the GqöPKC pathway. Mutations in the GsA gene that occur early in development result in the M cCune2A lb righ t syndrome, which is associated with a variety of tissues, such as multiple osteofibrous dysplasias, autoimmune precocious puberty, café-au-lait chromosome, autoimmune thyroid or adrenal nodules, and a predisposition to develop pituitary GH adenomas. GH adenomas of the pituitary gland. If the mutation in the gsA gene occurs late in development, it affects only a few tissues, such as the thyroid or pituitary nodules.1 1.2 R as oncogene Ras is also a GTPase. There are three homologous ras proto-oncogenes, H2ras, K2ras, and N2ras, which are called P21ras monomeric proteins, belonging to the small G-protein family, and have GTPase activity. missense mutations in two specific sites 12ö13 and 61 of the ras gene have transformed it into an oncogene. This mutation is frequent in some carcinomas, e.g., 30% of thyroid tumors. However, it is so far rare in pituitary adenomas and can only be used as a biological marker for highly aggressive pituitary tumors4 ]. Pituitary tumor-transforming (p itu itary tumo r2t ran sfo rm inggene (p ttg ) gene This gene consists of 199 amino acids and is a tumor-transforming gene that can induce tumor formation. It was first discovered by Pei and Melm ed in 1997. However, p ttg is not expressed in the normal pituitary gland. It is now believed that p ttg is a biological marker for the aggressiveness of pituitary adenomas. Recently, another p ttg family gene, p ttg 2, has been cloned from pituitary adenoma tissues, and its function has yet to be further elucidated.1,2 Oncogenes and pituitary adenomas Oncogenes are one of the most important protective mechanisms against tumorigenesis, and their intact bioactivity is effective in preventing tumorigenesis. Type 1 multiple endocrine adenoma (m u lt ip le endocrineneop lasia2É ,m en2É ) gene This is the gene for an autosomal dominant disorder. Patients develop endocrine tumors of the parathyroid glands, anterior pituitary gland, pancreatic islet cells, and thyroid and adrenal glands at the same time. The m en2É gene has recently been found to be located on the long arm of chromosome 11, region 13 (11q13). About 20% of sporadic pituitary adenomas have heterozygous deletion at 11q13, suggesting that inactivation of the oncogene in the 11q13 region may be responsible for the development of hereditary and sporadic endocrine tumors associated with m en2É. In 1997, Chandrasekharappa et al. cloned the m en2É gene, which has been named the m en in gene. The m en in gene has been reported to be the initiating factor for most pituitary adenomas of monoclonal origin. The retinoblastoma (ret inob lastom a, rb) gene The R b gene is an important regulatory protein of the cell cycle. Inactivation of the two alleles of rb on chromosome 13q14 produces RB tumors. Immunohistochemical studies have shown significant expression of Rb protein in benign ACTH adenomas but not in malignant ACTH adenomas and their metastases, suggesting that the rb gene may play an important role in the transition of benign pituitary ACTH adenomas to malignant ones. Purine-binding factor (nm 23) gene In invasive pituitary adenomas, the expression of the H2 isoform of the nm 23 gene is markedly reduced and is associated with cavernous sinus infiltration of the tumor, suggesting that the gene may be another oncogene implicated in the development of pituitary tumors. 1.3 Cyclin-dependent kinase (CDK) inhibitors Oncogene p 16 CDK ( The cyclin2dependent kinase (CDK) complex plays a key role in cell cycle regulation. p 16 is a specific repressor of CDK4. p 16 is located on human chromosome 9p 21 and consists of three exons and two introns. p 16 protein, the functional product of the p 16 gene, competes with cyclin for binding to CDK4 and prevents the phosphorylation of Rb protein. The functional product of the p 16 gene, P16 protein, competes with cyclin for binding to CDK4 and prevents the phosphorylation of Rb protein, thus preventing the cell from entering the S phase from the G1 phase and inhibiting cell growth. There are many mechanisms that lead to the loss of the functional product of the p 16 gene, such as deletion, mutation, methylation, and variations in the transcriptional and translational levels of the p 16 gene regulators, etc. When the methylation of the oncogene p 16 occurs, it is not possible to control the cell growth. When the oncogene p16 is methylated, it cannot synthesize oncoproteins by normal transcription and translation and exerts oncogenic effects, and the cells may undergo monoclonal proliferation and form tumors. Pituitary adenoma is a common tumor of monoclonal origin. In recent years, it has been proved that the incidence of CPG island methylation of p 16 gene in pituitary adenomas is as high as 70%～80%, suggesting that inactivation of p 16 gene methylation plays an important role in the development of pituitary adenomas. Oncogene p 27 P 27 is another CDK inhibitor, which can inhibit cell cycle progression, but no mutation of p 27 gene has been found in pituitary adenomas so far. Transcription factors and pituitary adenomas Transcription factors can be classified into four major groups according to their structure: (1) helix2loop 2helix transcription factors, such as P it21öGHF21 (P it21); (2) zinc finger proteins, such as estrogen and other steroid hormone receptors; (3) helix2loop 2helix, such as the c2my c oncogene; (4) leucine zipper structure, which can inhibit cell cycle progression, but so far no mutations in the p 27 gene have been found in pituitary adenomas. (4) Leucine zipper structural proteins, such as the c2f os oncogene. In pituitary PRL adenomas, GH adenomas and anaplastic adenomas, there is expression of estrogen receptor (est rogen receptor to r (ER)), and ER can regulate the expression of c2f os gene. c2my c is expressed in pituitary adenomas and normal pituitary tissues, but the significance of c2my c in tumorigenesis is not clear. The neuroendocrine tumor marker gene IA 21, a transcription factor with zinc finger structure, is expressed in some endocrine tumors such as pituitary adenomas, but not in normal tissues, suggesting that it may be related to the occurrence of endocrine tumors. 3. Receptors expressed in pituitary adenoma cells and their significance Under normal conditions, growth hormone releasing hormone (GHRH) secreted by the hypothalamus promotes the secretion of GH by pituitary GH cells, and growth hormone inhibitory factor (GHIF) secreted by the hypothalamus and growth mediator (somatom edine, SM) or insulin-like growth factor (IGGF) secreted by liver are also expressed in pituitary adenoma cells, suggesting that it may be related to the development of endocrine tumors. GH secretion is inhibited by growth hormone inhibitory factor secreted by the hypothalamus and by somatom edine (SM) or insulin-like growth factor 1 (in su lino id grow th fac2to r21, IGF21) secreted by the liver. TRH receptors are expressed in all types of pituitary adenomas, so that administration of TRH to patients with GH adenomas and nonfunctioning adenomas induces secretion of GH and the A and B subunits of the glycoprotein hormones. Epidermal growth factor (EGF) is expressed in most pituitary adenomas, suggesting that EGF may play a role in invasive pituitary adenomas through the EGF receptor. Growth factors and pituitary adenomas It is currently believed that growth factors are not the original triggering factors in the development of pituitary adenomas, but may play an important role in transformed pituitary adenoma cells. Basic fibroblast growth factor 2 (basic f ib rob lastgrow th facto r22, bFGF22) bFGF22 stimulates PRL secretion in both normal pituitary and pituitary adenoma cells. Human pituitary adenoma tissues express bFGF22, but no cytokinesis-promoting effect of bFGF was found in vivo. Although bFGF22 is abundantly expressed in the pituitary cells of transgenic mice, it does not form pituitary adenomas. 4.2 Transforming growth factor (t ran sfo rm ing grow th facto r2A, TGF2A) TGF2A is a peptide-like secretory protein composed of 50 amino acids. TGF2A is a 50-amino-acid peptide secreted protein that promotes mitosis when it binds to the EGF receptor in the cell membrane. TGF2A is expressed in normal pituitary PRL cells and pituitary adenomas. The high expression of TGF2A in the pituitary tissue of TGF2A transgenic mice induced the proliferation of pituitary PRL cells, which ultimately led to the formation of PRL adenomas, suggesting that TGF2A may play an important role in PRL adenoma development. Glycopeptide (galan in ) Glycopeptide is a pituitary hormone, which has paracrine and autocrine regulation of some pituitary hormones. Estrogen induces the expression of galanin. In estrogen-induced pituitary PRL adenomas, the expression of ghrelin is significantly elevated. Glycopeptide and GH expression and secretion were significantly increased in pituitary GH cells of human GH RH transgenic mice. Adrenocorticotropic hormone-releasing hormone (CRH) can promote the secretion of glycopeptide, and in vitro culture also proved that CRH promotes the secretion of glycopeptide in ACTH adenoma cells, but CRH does not promote the secretion of glycopeptide in normal human beings. However, CRH does not promote the secretion of glucagon-like peptide in normal human beings. The expression and secretion of glucagon-like peptide in the pituitary gland of rats were significantly increased after the administration of estrogen, but PRL adenomas were not necessarily formed. This suggests that glucagon-related peptides do not play an active role in the development of pituitary adenomas, but rather play an important role in promoting the monoclonal expansion of transformed pituitary adenoma cells.