Causes and pathogenesis of the syndrome of persistent galactorrhea-amenorrhea

The genesis of pathological hyperprolactinemia is not uniform. It is assumed that the basis of the syndrome of persistent galactorrhea-amenorrhea due to the primary lesion of the hypothalamic-pituitary system is the violation of tonic dopaminergic inhibitory control of prolactin secretion.

The concept of primary-hypothalamic genesis suggests that a decrease or absence of the inhibitory effect of the hypothalamus on the secretion of prolactin leads first to hyperplasia of prolactotrophs, and then to the formation of prolactin in the pituitary gland. The possibility of persistence of hyperplasia or micropropactinoma, which does not transform into the subsequent stage of the disease (that is, into macroprolactinum - a tumor that extends beyond the Turkish saddle) is permissible. At present, the hypothesis of primarily pituitary organic lesions (adenomas), which is not detected in the early stages by conventional methods, dominates. This adenoma is monoclonal and is the result of a spontaneous or induced mutation, as the promoters of tumor growth may act as releasing hormones, multiple growth factors (transforming growth factor-alpha, growth factor of fibroblasts, etc.) imbalance between regulatory influences. Moreover, excess prolactin entails the production of surplus dopamine by the neurons of the tubero-infundibular system.

Since the syndrome of persistent galactorrhea-amenorrhea often develops against a background of chronic intracranial hypertension and many patients have signs of endocraniasis, one can not exclude the role of neuroinfection or trauma of the skull, including in the perinatal period, as the causes of the inferiority of hypothalamic structures.

The role of emotional factors in the formation of the syndrome of persistent galactorrhea-amenorrhea is studied. It is possible that negative emotions, especially in the pubertal period, can cause stress hyperprolactinaemia and anovulation.

Although single cases of development of galactorrhea in sisters are described, there is no convincing evidence in favor of the existence of a hereditary predisposition,

In addition to the syndrome of persistent galactorrhea-amenorrhea as an independent disease, hyperprolactinaemia can develop again for various endocrine and non-endocrine diseases, and hypogonadism is mixed in nature and is caused not only by hyperprolactinaemia, but also by concomitant disease. Organic damage to the hypothalamus (xanthomatosis, sarcoidosis, histiocytosis X, hormone-inactive tumors, etc.) can cause a disruption in the synthesis or isolation of dopamine from tuberoinfundibular neurons. Any process that disrupts the transport of dopamine by axons to portal vessels or interrupts its transport through capillaries leads to hyperprolactinaemia. The compression of the pituitary foot by the tumor, the inflammatory process in this area, the transection of it, etc., are the etiological factors in the development of hyperprolactinaemia.

In some patients, there is a syndrome of "empty Turkish saddle" or cyst in his area. Perhaps the coexistence of the syndrome of the "empty" Turkish saddle and microadenoma of the pituitary gland.

Secondary symptomatic forms of hyperprolactinemia are observed in conditions accompanied by excessive production of sex steroids (Stein-Leventhal syndrome, congenital adrenal cortex dysfunction), primary hypothyroidism, intake of various medications, reflex effects (presence of intrauterine contraceptives, burns and chest injuries), chronic renal and hepatic insufficiency. Until recently, it was assumed that prolactin is synthesized exclusively in the pituitary gland. However, immunohistochemical methods of investigation made it possible to detect the presence of prolactin in tissues of malignant tumors, intestinal mucosa, endometrium, decidual membrane, granulosa cells, proximal tubules of the kidneys, prostate, adrenal glands. Presumably, extrhypophilic prolactin can act as a cytokine, and its paracrine and autocrine effect is no less important for providing vital activity to the organism than well-studied endocrine effects.

It has been established that the decidual cells of the endometrium produce prolactin, which in its chemical, immunological and biological properties is identical to the pituitary. Such local synthesis of prolactin is determined with the initiation of the process of decidualization, increases after implantation of a fertilized egg, reaches a peak at 20-25 weeks of pregnancy and decreases immediately before childbirth. The main stimulating factor of decidual secretion is progesterone, classical regulators of pituitary prolactin - dopamine, VIP, tyroliberin - in this case no real effect.

Virtually all molecular forms of prolactin are found in the amniotic fluid, the source of its synthesis is decidual tissue. Hypothetically, decidual prolactin prevents blastocyst rejection during implantation, suppresses contractile activity of the uterus during pregnancy, promotes the development of the immune system and the formation of a surfactant in the fetus, and participates in osmoregulation.

The value of prolactin production by myometrium cells remains unclear. Of particular interest is the fact that progesterone has an inhibitory effect on prolactin-secreting activity of muscle cell cells.

Prolactin is found in human breast milk and a number of mammalian animals. Accumulation of the hormone in the secretion of the mammary glands is due to both its transport from the surrounding alveolar cells of the capillaries, and local synthesis. At present, there is no convincing correlation between the level of circulating prolactin and the incidence of breast cancer, but the presence of local hormone production does not completely exclude its role in the development or, on the contrary, inhibition of the development of these tumors.

The presence of prolactin is determined in cerebrospinal fluid even after hypophysectomy, which indicates the possibility of prolactin production by neurons of the brain. It is assumed that in the brain the hormone can perform many functions, including ensuring the consistency of the CSF composition, mitogenic effects on astrocytes, controlling the development of various releasing and inhibitory factors, regulating the change in sleep and wake cycles, and modifying the eating behavior.

Prolactin is produced by the skin and the exocrine glands associated with it; fibroblasts of connective tissue are a potential source of local synthesis. In this case, researchers believe that prolactin can regulate the concentration of salt in the sweat and tear fluid, stimulate the proliferation of epithelial cells, and enhance hair growth.

It has been established that human thymocytes and lymphocytes synthesize and secrete prolactin. Virtually all immunocompetent cells express prolactin receptors. Hyperprolactinemia is often accompanied by autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroiditis, diffuse toxic goiter, multiple sclerosis. The level of the hormone exceeds the norm and in most patients with acute myelogenous leukemia. These data suggest that prolactin plays the role of immunomodulator.

Hyperprolactinemia, probably extrhypophysis genesis, is often present in a number of oncological diseases, including cancer of the rectum, tongue, cervix, lungs.

Chronic hyperprolactinemia disrupts the cyclic release of gonadotropins, reduces the frequency and amplitude of the "peaks" of LH secretion, inhibits the action of gonadotropins on the sex glands, which leads to the formation of a hypogonadism syndrome. Galactorrhea is a frequent but not an obligatory symptom.

Patanatomy. Despite the numerous data that testify to the wide spread of the microaden in the radiologically intact or having minimal, uncharacteristic changes in the Turkish saddle, a number of researchers admit the possibility of the existence of so-called idiopathic, functional forms of hyperprolactinemia caused by hyperplasia of prolactotrophs due to hypothalamic stimulation. Hyperplasia of prolactotrophs without the formation of a microaden was often observed in remote adenohypophysis patients with persistent galactorrhea-amenorrhea syndrome. There are cases of postpartum lymphocytic infiltration of adenohypophysis leading to the emergence of a syndrome of persistent galactorrhea-amenorrhea. Probably, different options for the development of this syndrome are possible.

According to light microscopy, most prolactinomas consist of the same type of oval or polygonal cells with a large oval nucleus and a convex nucleolus. With conventional staining methods, including hematoxylin and eosin, prolactinomas often look chromophobic. Immunohistochemical examination showed a positive reaction to the presence of prolactin. In some cases, tumor cells are positive for STH-, ACTH- and LH-antisera (at a normal level of these hormones in the blood serum). Based on electron microscopic studies, two subtypes of prolactin are distinguished: the most characteristic are rarely granulated with a granule diameter of 100 to 300 nm and densely granulated, containing granules up to 600 nm in size. The endoplasmic reticulum and the Golgi complex are well developed. The presence of calcium inclusions - microcalciferites - often allows you to refine the diagnosis, because in other species of adenomas, these components are extremely rare.

True chromophobic adenomas (hormoneally inactive tumors of the pituitary gland) can be accompanied by a syndrome of persistent galactorrhea-amenorrhea due to prolactin hypersecretion by prolactotrophs surrounding the adenoma. Sometimes hyperprolactinaemia is observed with hypothalamic and pituitary diseases, in particular with acromegaly, Isenko-Cushing's disease. In this case, either two types of cells or pluripotent adenomas that can secrete several hormones are detected. Less often is the coexistence of two or more adenomas from cells of different types, or the source of excessive secretion of prolactin is the tissue surrounding the adenohypophysis.

[1], [2], [3], [4], [5], [6], [7]