Causes and pathogenesis of acromegaly and gigantism

The vast majority of cases of the disease are sporadic, but cases of familial acromegaly have been described.

The theory of pituitary syndrome was put forward as early as the end of the 19th century. Subsequently, mainly domestic researchers demonstrated the inconsistency of localistic concepts about the exclusive role of the pituitary gland in the pathogenesis of the disease using large clinical materials. It was proven that primary pathological changes in the diencephalon and other parts of the brain play a significant role in its development.

A characteristic feature of acromegaly is increased secretion of growth hormone. However, a direct relationship between its content in the blood and clinical signs of disease activity is not always observed. In approximately 5-8% of cases, with a low or even normal level of somatotropic hormone in the blood serum, patients have pronounced acromegaly, which is explained either by a relative increase in the content of a special form of growth hormone with high biological activity, or an isolated increase in the level of IGF.

Partial acromegaly, which is characterized by an increase in individual parts of the skeleton or organs, is usually not associated with excess secretion of growth hormone and is a congenital local tissue hypersensitivity.

The literature describes a wide range of pathological and physiological conditions that have a direct or indirect relation to the development of acromegaly. These include psychoemotional stress, frequent pregnancies, childbirth, abortions, climacteric and post-castration syndromes, extra-pituitary brain tumors, head injuries with concussion, the influence of specific and non-specific infectious processes on the central nervous system.

Thus, the causes of acromegaly as a syndrome may be primary pathology of the hypothalamus or overlying parts of the central nervous system, leading to stimulation of the somatotropic function and hyperplasia of pituitary cells; primary development of a tumor process in the pituitary gland with autonomous hypersecretion of somatotropic hormone or its active forms; an increase in the content or activity of IGF in the blood, which directly affects the growth of the bone and joint apparatus; increased sensitivity to the action of somatotropic hormone or IGF of peripheral tissues; tumors secreting somatotropic hormone or STH-releasing factor and ectopic in other organs and tissues of the body - lungs, stomach, intestines, ovaries.

Pathological anatomy

The main cause of acromegaly and gigantism are pituitary adenomas of somatotrophs and somatotropin- and prolactin-secreting cells, the ratio of which varies from case to case. There are two types of pituitary adenomas that produce somatotropic hormone: acidophilic cell adenomas (richly granulated and weakly granulated) and chromophobe adenomas. Very rarely, somatotropinomas are oncocytic cell tumors.

Acidophilic cell adenoma is an encapsulated or unencapsulated benign tumor, usually consisting of acidophilic cells, less often with an admixture of large chromophobe cells or transitional forms. Tumor cells form cords and fields separated by a richly vascularized stroma. They are identified at the level of light microscopy, ultrastructurally and immunocytochemically as somatotrophs with numerous secretory granules with a diameter of 300-400 nm. Some cells contain large nucleoli, intensively developed endoplasmic reticulum and a small number of secretory granules, which reflects their high secretory activity.

Chromophobe pituitary adenomas cause the development of acromegaly or gigantism in an average of 5% of patients. They are poorly granulated tumors. The cells that form them are smaller than acidophilic ones, the cytoplasm is scanty with a small number of electron-dense granules 80-200 nm in diameter with an electron-dense membrane and a perigranular areola. The cell nucleus is compact and contains nucleoli. The largest cells include a large number of secretory granules, although fewer than in acidophilic adenomas. Chromophobe adenomas of solid or trabecular structure occupy the lower lateral part of the pituitary gland. Cases have been described where chromophobe adenomas with ultrastructural features of TSH-producing cells, but also secreting somatotropic hormone, underlie the development of acromegaly.

In some patients with acromegaly and gigantism, due to hypersecretion of STH-RH by the hypothalamus, diffuse or multifocal hyperplasia of acidophilic cells occurs in the pituitary gland. Acromegaly can also develop in patients with apudomas of various localizations, with islet cell tumors that produce either somatotropic hormone or STH-RH, which stimulates the somatotrophs of the adenohypophysis. Sometimes it has a paracrine effect, stimulating the formation of somatotropic hormone by the tumor cells themselves. STH-RH is also produced by gangliocytomas of the hypothalamus, oat cell and squamous cell lung cancers, and bronchial carcinoid.

About 50% of patients with acromegaly have an enlarged nodular thyroid gland, which may be due to hyperproduction of TSH by tumor cells.

Patients with acromegaly and gigantism show splanchnomegaly caused by hypertrophy of parenchymatous structures and excessive growth of fibrous tissue. Hypertrophy of the adrenal glands in some patients is associated with hyperproduction of ACTH by both tumor cells and paraadenomatous pituitary tissue. Bone growth and pathological changes in them are caused by high functional activity of osteoblasts. In the late stage of the disease, they resemble changes in Paget's disease.

Patients with acromegaly belong to the risk group for polyps and bowel cancer. They are found in more than 50% of patients and are combined with skin stigmas (papillomatosis), which are external markers of colon polyps.