What are intermittent headaches?

Headache is a relatively common disease in our lives. Generally, there are many causes of headaches, including neuralgia, headaches caused by high blood pressure, headaches caused by cervical spondylosis, and colds. No matter what the cause of the headache is, it will affect our normal life and work. It is best to treat indirect headaches in time to avoid worsening of the condition.

Causes of intermittent headaches

Non-functioning pituitary adenomas are actually a group of heterogeneous tumors, most of which have division function (mostly gonadotropin), but their secretion function is low and does not cause an increase in blood hormone levels. This type of tumor is called silent adenoma.

Some non-functioning adenomas may indeed have no secretory function, and their cell origin is unclear, which is called naked cell tumor or null cell adenoma.

Pathogenesis

There have been two theories in the study of the pathogenesis of pituitary tumors, namely the pituitary cell defect theory and the hypothalamic regulation disorder theory. It is now basically agreed that the development of pituitary tumors can be divided into two stages: the initial stage and the promotion stage.

In the initial stage, defects in pituitary cells themselves are the main cause of the disease, while in the promotion stage, factors such as hypothalamic regulation disorders play a major role. That is, a pituitary cell mutates, leading to the activation of oncogenes and/or the inactivation of tumor suppressor genes. Then, under the promotion of internal and external factors, the monoclonal mutant cells continue to proliferate and gradually develop into pituitary tumors.

1. Intrinsic defects of pituitary tumor cells

The use of molecular biological techniques has now made it clear that most functional and non-functional adenomas are monoclonal, originating from the unrestricted proliferation of a single mutant cell. The causes of mutation are activation of oncogenes and/or inactivation of tumor suppressor genes.

The main oncogenes that have been identified include gsp, gip, ras, hst and PTTG, and the tumor suppressor genes include MEN-1, p53, Nm23 and CDKN2A. The gsp gene was found in 40% of GH tumors, 10% of non-functioning adenomas, and 6% of ACTH tumors.

The activation of the gsp gene and the gip2 gene inhibits the activity of endogenous GTPase, so that the α-subunit of the Gs protein and the Gi2 protein are continuously activated. The latter two can be regarded as the products of the gsp oncogene and the gip2 oncogene, respectively.

These two oncogene products can directly cause the activation of nuclear transcription factors such as AP-1, CREB and Pit-1, increasing hormone secretion and initiating tumor growth.

In addition, the activation of oncogenes will lead to an increase in intracellular cAMP levels, which can stimulate cyclin (cell cycle protein) DL and 3 to produce cdk2 and cdk4, the latter two of which can promote cells to enter the S phase from the G1 phase.

Increased cAMP levels can also induce activation of the ras oncogene. The ras oncogene and cmyc gene work synergistically to prevent the binding of pRb and F2F, because the binding of the latter two will hinder the cell cycle. Preventing the binding of the two will accelerate the cell's entry from the G1 phase to the S phase.

The inactivation of tumor suppressor genes such as MEN-1 is caused by the deletion of the allele at locus 13 (11q13) on the long arm of chromosome 11. The pathogenesis of various pituitary tumors involves the inactivation of the tumor suppressor gene P16/CDKN2A, and the frequent methylation of the CpG island of this gene is the cause of its inactivation.

Therefore, it may be possible to develop a treatment method in the future to demethylate the CpG island of tumor suppressor genes, restore their tumor suppressor effect and achieve the treatment goal.

2. Paracrine and autocrine dysfunction

Hypothalamic pituitary stimulating hormone and paracrine or autocrine hormones in the pituitary may play a role in the promotion stage of pituitary tumor formation. GHRH promotes GH secretion and GH cell mitosis. Ectopic tumors that secrete GHRH can cause pituitary GH tumors.

GHRH promotes GH secretion and GH cell mitosis

Animals implanted with the GHRH gene can cause GH cell proliferation, which in turn induces pituitary tumors. All of the above indicate that increased GHRH can induce the formation of pituitary tumors. Certain growth factors such as FTH-related peptide (PTHrP), platelet-derived growth factor (PDGF), transforming growth factors α and β (TGF-α and TGF-β), IL, IGF-1, etc. are expressed at high levels in different pituitary tumors. They may promote the growth and differentiation of pituitary tumor cells in a paracrine or autocrine manner.

The lack of nerve growth factor (NGF) promotes the occurrence and development of PRL tumors. During the development stage of the normal pituitary gland, NGF promotes the differentiation and proliferation of prolactin cells.