The pronounced proliferation of the endometrium against the background of systemic immunosuppression and enhanced angiogenesis, accompanied by a local inflammatory reaction, are the essence of the disease. Functional endometrium penetrates by invasion into the myometrium (adenomyosis), spreads from uterine cavity to uterine pipes, ovaries and along the peritoneum of the Douglas space. It is possible to transfer endometrioid tissue with blood and lymph into distant organs and tissues (eyes, navel). Of course, for such expansion, the endometrium should be endowed with a strong proliferative potential and a high sensitivity to estrogen stimulation.
At the cellular level, a sequence of events is established, leading to the development of a high intracellular concentration of estradiol, which plays a key role in the development of the disease. This process is based on gene polymorphism (DNA structure variability) that provide high activity of various cytochromes and transferases. At the first stage, active local production of the aromatase enzyme (cytochrome CYP19) takes place in endometrial cells, which stimulates the conversion of C-19 steroids into estrogens. The latter through the system of cyclogenases induce the production of prostaglandins, which, in turn, support the high activity of aromatase. Under these conditions, the level of estradiol receptors in endometrial cells increases, which provide intracellular intake and intranuclear translocation of this steroid. Estradiol provides a high proliferative potential of the endometrial epithelium. Endometrial cells proliferate, forming foci of ectopy and invasion into underlying structures, which leads to pain and general emotional and physical discomfort. Menstrual irregularities and primary infertility often accompany the disease, but are not necessarily attributes of suffering.
Endometriosis is a disease with a pronounced estrogenic dependence. This is confirmed by clinical observations. The development of the disease is noted in the reproductive period, its peak is at the age of 25-35 years. The positive effect of progestin therapy used in adequate doses was noted, which leads to a significant alleviation of the symptoms of the disease and a regression of endometrioid heterotopies in the form of hypoplasia epithelium with a gradual replacement of its fibrous tissue. The appointment of gonadotropin agonists, which significantly reduces the estrogenic background in the patient’s body and causes a condition of amenorrhea, also allows achieving remission of the disease.
Clinical manifestations of the disease can not be combined with certain disorders in the immune system of the body. Indeed, endometriosis is associated with changes in both T-cell and humoral immunity. Despite the fact that the peritoneal fluid contains a large number of immunocompetent cells, there is not an inhibition but an endometriosis stimulation. Reduced activity of a large number of leukocytes leads to the inability to eliminate endometrioid cells. And simultaneously observed proliferation of endometrial epithelium under the influence of growth factors, cytokines and estrogens leads to the progression of the disease.
Macrophages are the main cells of innate immunity, the activity of which depends on the outcome of inflammation and many other cellular reactions at the systemic level. Another important function of macrophages in endometriosis is the removal of cellular debris and cells that have undergone apoptosis. In other words, here macrophages play the role of “scavengers” that remove the resulting inert protein from the body and the ectopic endometrium. Macrophages are the most numerous cell types found in peritoneal fluid in patients with endometriosis. However, their function of “scavengers” in these patients is sharply weakened. One of the reasons for this is a disturbance of the interaction of macrophages with the extracellular matrix. When this interaction is not observed, macrophages lose the ability to play the role of competent “scavengers”.
Another factor regulating the intensity of cellular and humoral immunity is lymphocytes. The greatest changes in the pool of T-lymphocytes in the peritoneal fluid in endometriosis were noted. There is an increase in the number of both helpers and suppressors. According to immunohistochemical analyzes, the number of T-lymphocytes determined in the stroma of the ectopic endometrium, in women who did not suffer from endometriosis, it was increased in comparison with the number of T cells in the proliferative and secretory eutopic endometrium. The latter allows to draw a conclusion about the key role of the T-system of immunity in “restraining” the proliferation of endometrial epithelium and its “expansion” into adjacent organs.
For the sake of objectivity, it should be noted that the “multifactor” in explaining the etiopathogenesis of endometriosis undoubtedly disguises the fact that until now the true mechanism that triggers the development of the disease remains undisclosed.
Benign hyperplasia of myometrium (uterine myoma)
A significant number of studies have been devoted to various aspects of the pathogenesis of uterine myoma, including the characterization of hereditary factors, the evaluation of disorders of the pituitary-ovarian function, and the data on morphological and histochemical changes revealed in myometrium and ovaries in patients. A significant number of recent studies (which is continuously increasing) is devoted to the quantitative determination of hormonal receptors for estradiol and progesterone in tumor tissue and in myometrium, allowing us to clarify the mechanism of the effect of estradiol and progesterone at the cellular level.
Clinical observations of the stimulating effect of estrogens on the development of the uterus in its infantilism, supported by experimental data showing the possibility of induction of fibroids with prolonged administration of estrogens, served as convincing evidence for the role of hyperestrogenia in the development of benign hyperplasia of myometrium. According to our research, clinico-morphological signs of hyperestrogeny were revealed in 853 patients with uterine myoma at a high rate: acyclic uterine bleeding (37.9%), later onset of menopause (after 56 years) – 35.1%, hyperplasia of hormone-producing ovarian tissue – follicular ovarian cysts in the reproductive period (30.6%), stromal hyperplasia in pre- (52.2%) and postmenopausal (62.7%). Estrogenic type of colpositologic reaction in postmenopause (30.6%) and obesity (54.2%) are noted as a marker of increased estrogenic background due to metabolic (aromatization) conversion of androstenedione into estrone in adipose tissue, which increases the estrogen pool in the patient’s body.
Thus, modern ideas about the mechanism of development of hyperestrogenism are not limited only to analysis of the violations that cause anovulation. It is shown that there are several facts that clearly show that hyperestrogenism can be considered as a factor in the pathogenesis of muscle hyperplasia in a certain number of patients with uterine myoma. This is, first of all, epidemiological data, where there is a temporary coincidence of peaks in the incidence of hyperplastic processes of the myometrium and endometrium, for which the role of excessive estrogenic influence is not contested.
Further, the data on local hyperestrogeny in the system of uterine arteries feeding the myometrium and tumor, as well as the increased content of cytosolic receptors for estradiol found in myoma tissue, are convincing.
Finally, the hormone dependence of uterine fibroids is proved “by contradiction” with clinical observations of the possibility of partial or complete regression of the “tumor” when the patient is prescribed a gonadotropin (zoladex) agonist or progesterone receptor blocker (Myfolian).
Strictly speaking, uterine myoma is a monoclonal proliferative that retains sensitivity to hormonal influence and consists of phenotypically altered smooth muscle cells of myometrium that immunohistochemically correspond to such benign entities as fibroma, lipoma or keloid scar. Apparently, therefore, in the present there is a decrease in unjustifiably high oncologic alertness to the uterine myoma, as it is proved that this cell proliferate has a malignancy potential comparable with the normal myometrium.