Causes and pathogenesis of panhypopituitarism

Hormonal deficiency of the hypothalamic-adenohypophyseal system develops due to infectious, toxic, vascular (for example, in systemic collagen diseases), traumatic, tumor and allergic (autoimmune) lesions of the anterior pituitary gland and/or hypothalamus.

A similar clinical syndrome also occurs as a result of radiation and surgical hypophysectomy. Any infection and intoxication can lead to dysfunction of the hypothalamic-adenohypophyseal system. Tuberculosis, malaria, syphilis in the recent past often caused destructive processes in the hypothalamus and pituitary gland with subsequent development of Simmonds syndrome. A decrease in the overall incidence of these chronic infections has reduced their role in the occurrence of hypothalamic-pituitary insufficiency.

The disease may be preceded by influenza, encephalitis, typhus, dysentery, purulent processes in various organs and tissues with thromboembolic complications and pituitary necrosis, craniocerebral trauma accompanied by intracerebral hemorrhages in the hypothalamus or pituitary gland with the formation of cysts as a result of hematoma resorption. The development of hypopituitarism may be based on fungal infections, hemochromatosis, sarcoidosis, primary and metastatic tumors.

One of the most common causes of the disease in women is abortion and especially childbirth complicated by eclampsia in the last months of pregnancy, sepsis, thromboembolism, massive (700-1000 ml) blood loss, which leads to impaired circulation in the pituitary gland, angiospasms, hypoxia and necrosis. Repeated and frequent pregnancies and childbirth, as factors of functional stress of the pituitary gland, can contribute to the development of hypopituitarism. In recent years, hypothalamic-pituitary insufficiency in women with severe toxicosis in the second half of pregnancy in some cases is associated with the development of autoimmune processes (autoaggression). Evidence of this is the detection of autoantibodies to the extract of the anterior pituitary gland.

Although rare, ischemic changes in it can also occur in men after gastrointestinal and nasal bleeding and as a result of systematic, long-term donation.

In a number of patients, the cause of hypopituitarism cannot be identified (idiopathic hypopituitarism).

Regardless of the nature of the damaging factor and the nature of the destructive process ultimately leading to atrophy, wrinkling and sclerosis of the pituitary gland, the pathogenetic basis of the disease in all clinical variants of hypothalamic-pituitary insufficiency is a decrease or complete suppression of the production of adenohypophyseal tropic hormones. This results in secondary hypofunction of the adrenal, thyroid and sex glands. In rare cases of simultaneous involvement of the posterior lobe or pituitary stalk in the pathological process, a decrease in the vasopressin level with the development of diabetes insipidus is possible. It should be taken into account that a simultaneous decrease in ACTH and corticosteroids, antagonists of vasopressin in relation to water metabolism, can level out and mitigate the clinical manifestations of vasopressin deficiency. However, a decrease in its activity in response to osmolar load is noted in patients with Sheehan syndrome and in the absence of clinical signs of diabetes insipidus. Against the background of replacement therapy with corticosteroids, manifestation of diabetes insipidus is possible. Depending on the localization, extent and intensity of the destructive process, uniform, complete (panhypopituitarism) or partial, when the production of one or more hormones is preserved, loss or decrease of hormone formation in the pituitary gland is possible. Very rarely, in particular with empty sella syndrome, there may be isolated hypofunction of one of the tropic hormones.

A decrease in the production of growth hormone, and consequently its universal effect on protein synthesis, leads to progressive atrophy of smooth and skeletal muscles and internal organs (splanchnomycosis). There is a concept that it is the involvement of hypothalamic nuclei in the pathological process that determines the speed of development and severity of exhaustion.

Defect of prolactin synthesis leads to agalactia. Along with this, posttraumatic hypothalamic panhypopituitarism with loss of prolactin-inhibiting factor can be combined with high prolactin levels. Hyperprolactinemia and hypopituitarism are observed in malignant prolactinomas.

Transient or persistent hypopituitarism, partial or complete, may complicate surgical or radiation treatment of pituitary and hypothalamic tumors. Hypophysectomy surgery is also sometimes performed to suppress counter-insular hormones in patients with severe, progressive diabetic retinopathy with the threat of vision loss.

Pathological anatomy

Panhypopituitarism develops when at least 90-95% of the pituitary tissue is damaged. Rarely, it is caused by pituitary aplasia due to congenital absence of the organ or a defect in the formation of Rathke's pouch. Sometimes only the anterior lobe of the gland is missing. Its congenital atrophy most often occurs due to compression of the pituitary gland by a cyst from Rathke's pouch.

Acute inflammation of the pituitary gland (purulent hypophysitis) as a cause of panhypopituitarism occurs due to septicemia or infection from adjacent areas. In these cases, abscesses may develop that destroy the pituitary gland. One of the rare causes of panhypopituitarism is lymphoid hypophysitis with massive lymphoid infiltration of the gland and replacement of pituitary tissue with lymphoid tissue, which can be combined with autoimmune diseases of other endocrine organs.

Granulomatous lesions of the pituitary gland of various etiologies are often accompanied by hypopituitarism due to the destruction of pituitary tissue. Tuberculosis of this endocrine organ occurs during dissemination of the process, and pathological changes in it are typical for tuberculosis of any localization. Syphilis of the pituitary gland develops either as a process of diffuse scarring or as a gummatous process that destroys glandular tissue.

Hypothalamic insufficiency due to syphilitic damage, sarcoidosis, giant cell granulomas, suprasellar metastases (pineal germinoma and other tumors) are possible causes of panhypopituitarism.

In generalized hemochromatosis and hemosiderosis, iron is deposited in the parenchymatous cells of the hypothalamus and pituitary gland, followed by destruction of these cells and development of fibrosis, most often in the anterior pituitary gland. In histiocytosis, X-xanthoma deposits and histiocytic-cell infiltrates are often found in both lobes of the pituitary gland. They cause destruction of glandular cells.

Chronic pituitary insufficiency may be caused by a functionally inactive chromophobe adenoma of the pituitary gland, intrasellar and extrasellar cysts, tumors: craniopharyngioma, glioma of the hypothalamus or optic chiasm, suprasellar meningioma, angioma of the pituitary stalk, etc. In all these cases, thrombosis of the portal vessels may be the main cause of destruction of pituitary tissue. Destruction of the infundibulum leads to complete necrosis of the anterior pituitary gland. The cause of necrosis of the adenohypophysis in Sheehan's syndrome is occlusive spasm of arterioles at the site of their entry into the anterior lobe; it lasts 2-3 hours, during which necrosis of the pituitary gland occurs. Resumption of blood flow through the vessels of the infundibulum does not restore circulation through the portal vessels damaged by ischemia. The intravascular coagulation syndrome that often accompanies postpartum hemorrhage leads to thrombosis of passively stretched vessels and to necrosis of a significant part of the pituitary gland, mainly the central part. A scar appears at this site, calcifying and even ossifying.

Familial hypopituitarism syndrome, associated with an enlarged sella turcica and the "empty sella turcica" syndrome, occurs as a result of a pituitary tumor present in childhood, which has undergone spontaneous regression over time, but has caused irreversible compression and atrophy of the adenohypophysis.

In people who died from pituitary failure, 1-2 to 10-12% of intact pituitary tissue is found. In the neurohypophysis, pronounced subcapsular atrophy and cicatricial changes are noted. In the hypothalamus (in the posterior, supraoptic and paraventricular nuclei), atrophic changes develop over time, and in the subventricular nuclei, neuronal hypertrophy. In the internal organs (in the heart, liver, spleen, kidneys, thyroid gland, gonads and adrenal glands), atrophic changes occur, sometimes with pronounced fibrosis.