The causes and pathogenesis of polycystic ovaries

The cause and pathogenesis of the polycystic ovary syndrome is unknown. Early knowledge of the leading role in the pathogenesis of sclerosis of the gallbladder that hampers ovulation is rejected, since it has been shown that its severity is an androgen dependent symptom.

One of the main pathogenetic links of the polycystic ovary syndrome, which largely determines the clinical picture of the disease, is the hyperandrogenia of ovarian genesis, coupled with a disruption of the gonadotropic function. Early studies of the level of androgens, or more precisely of their metabolites in the form of total and fractional 17-ketosteroids (17-CS), showed their significant variation in the syndrome of polycystic ovaries, from normal to moderately elevated. Direct determination of androgens in the blood (testosterone - T, androstenedione - A) by radioimmunological method revealed their constant and reliable increase.

In the 1960s, a number of researchers conducted studies on steroidogenesis in ovarian tissue in vitro. In the incubation of ovarian sections of polycystic ovaries with labeled A, V. V. Mahesh and R. V. W. Greenblatt discovered an excess accumulation of dehydropeandrosterone (DHEA). When added to incubate A, it rapidly transformed into estrogens, and after the addition of chorionic gonadotropin, the level of DHEA increased.

GF Erickson showed that both in the polystyrene ovaries and in the normal ovaries, excessive formation of testosterone (T) and androgens (A) occurs in small maturing follicles not reaching 6 mm in diameter, because in these follicles the granulosa cells have not yet reached maturity and did not show aromatase activity. According to the Falk bi-cellular theory, the synthesis of estrogens is performed in two stages in two groups of cells: in theca interna folliculi, synthesis occurs mainly to testosterone and A, and their aromatization into estrogens (E2 and E1) occurs in the granulosa. According to GF Erickson et al., In large follicles of healthy women and women with polycystic ovaries, granulosa cells have the same aromatase activity and aromatize T and A to E2 and E1 in equal amounts. The aromatic activity of granulosa cells is under the control of pituitary FSH. In addition, K. Savard, V. F. Rice showed that in both healthy and polycystic ovaries testosterone is a unique product of the stroma, and with its hyperplasia as a result of hyperstimulation by luteinizing hormone, the excess of testosterone in the blood is quite understandable. An additional source of androgens in the female body may be peripheral metabolism.

Most researchers have an increased level of luteinizing hormone in the polycystic ovary syndrome, a lack of an ovulatory peak, a normal or a decreased level of FSH. At this ratio of LH / FSH is always violated in the direction of predominance of luteinizing hormone. Violation of gonadotropic regulation is not limited only to the level of the hypothalamic-pituitary system. AD Dobracheva revealed a violation of the intra-ovarian interaction of the luteinizing hormone with the receptor, ie, at the first stage of gonadotropic regulation. A correlation of the level of ovarian T with the features of binding of the labeled luteinizing hormone in interstitial tissue of the ovaries was found. However, an elevated level of LH may not be associated with primary hypothalamic disorders, but is due to primary hyperandrogenism.

Thus, an increase in the level of luteinizing hormone does not lead directly to hyperandrogenia, but the excess of E2 formed as a result of peripheral metabolism (especially in adipose tissue) of androgens into estrogens (A-E1). Estrone (E1) sensitizes the pituitary gland to the LH-RG, which results in an increased secretion of luteinizing hormone.

The ovulatory peak of the latter is absent. Sensitization of the pituitary gland to LH-RG is confirmed by a breakdown with luliberin of 100 mcg iv, which reveals a hyperergic response of luteinizing hormone, but not FSH. A high level of luteinizing hormone causes hyperplasia of the ovarian stroma, which entails increased synthesis of ovarian androgens. In addition, theca interna folliculi under the conditions of anovulation and insufficient maturity of granulosa cells is also a source of androgens.

The start of this mechanism can be carried out in the prepubertal period, adrenarche, when there is an increase in adrenal androgens, independent of ACTH secretion, since there is no parallel increase in cortisol secretion at this time. Elevated levels of androgens can lead to an increase in estraglundular estrogen production, which in turn will cause the growth of LH / FSH. The androgenic basis of this syndrome then moves from the adrenal to the ovarian.

The role of the adrenal glands in the pathogenesis of the polycystic ovary syndrome is not limited to the adrenarche period. Numerous attempts to clearly delineate the adrenal and ovarian contribution of androgens through suppression and stimulation samples, the selective catheterization of the veins of the ovaries and adrenal glands has not produced any effect. Approximately 20% of patients with polycystic ovary syndrome have an elevated level of excretion of 17-CS, but it should be emphasized that this indicator reflects mainly the content of DHEA and A, rather than testosterone.

DHEA and its sulfate are the main adrenal androgens. Their suppression of dexamethasone in patients with polycystic ovary syndrome testifies to the adrenal genesis of hyperandrogenism. Levels of T (testosterone), A and 17-OH-progesterone are slightly suppressed by dexamethasone, indicating their ovarian origin. These studies suggest, but do not establish precisely, that hyperandrogenism in patients with polycystic ovary syndrome is mixed - adrenal and ovarian. In some patients with polycystic ovary syndrome, adrenal hyperplasia is identified. M. L. Leventhal indicates that significant secretion of androgens with polycystic ovaries can lead to partial blocking of the lip-hydroxylase enzyme system in patients with polycystic ovary syndrome. These findings are based on a greater increase in dehydroepiandrosterone (DHEA), 17-pregnenolone, progesterone and 17-OH-progesterone in patients with this syndrome in response to prolonged stimulation of ACTH. Many authors come to the conclusion that in the syndrome of polycystic ovaries there is a combined hyperandrogenism - ovarian and adrenal.

Another important pathogenetic link in virilization in women is a change in the binding of androgens with testosterone-estradiol-binding globulin (TESG). The transfer of hormones from their source to the destination occurs in a connected form. TESG is synthesized in the liver, its relative molecular weight is about 100,000. The highest binding capacity of TESG is found for DNT (three times higher than for T, and 9 times greater than for E2). A and DHEA are not linked by TESG. The concentration of testosterone-estradiol-binding globulin in the plasma of adult women is 2 times higher than that of men. This difference is caused by the fact that its production is stimulated by estrogens and suppressed by androgens. Therefore, women with hyperandrogenia have a lower concentration of TESG than healthy women. The degree of biological activity of androgens is determined by the level of free steroids (associated with TESG steroids are biologically inactive).

It should be remembered that an excess of glucocorticoids, an excess of STH, a deficiency of thyroid hormones lead to a decrease in the concentration of this globulin.

Thyroid hormones are the only ones, except E2, which stimulate the production of TESG.

In recent years, it has been found that in patients with polycystic ovaries in 20-60% of cases there is hyperprolactinaemia, which suggests dopaminergic anomalies in the hypothalamic-pituitary-ovarian system. There is an opinion that a high level of prolactin can increase adrenal hyperandrogenism. M.E. Quigley revealed a sharp decrease in elevated levels of LH after dopamine (DA) administration, i.e. In patients with polycystic ovaries, an increased sensitivity of luteinizing hormone to the inhibitory effect of DA was found. The findings suggest that an increase in LH levels may be associated with a lower endogenous dopaminergic effect on the secretion of luteinizing hormone in patients with polycystic ovary syndrome. Recent studies have shown that excess beta-endorphin production can play a role in the pathogenesis of the polycystic ovary syndrome, especially in the presence of a triad: amenorrhea-obesity-hyperandrogenia.

As SS S. Yen pointed out, there were reports that the syndrome can manifest as a disease inherited by the dominant type and associated with the X chromosome. In a number of patients, the disappearance of the long arm of the X chromosome, mosaicism, was noted. Nevertheless, most patients with polycystic ovary syndrome have a normal karyotype of 46 / XX.

Of special interest is a subgroup of patients with polycystic ovary syndrome in families with ovarian hypertension (tekomatosis), which is often clinically difficult to distinguish from polycystic ovary syndrome. Family forms of this disease testify in favor of genetic disorders. However, in the pathogenesis of tekomatosis in recent years, the role of insulin has been revealed. RL Barbieri showed that there is a close relationship between hyperandrogenia and hyperinsulinemia. Insulin, perhaps, takes part in ovarian steroidogenesis rights. In the incubates of the ovarian stroma of healthy women, LG plus insulin acted as agonists, stimulating the production of A and T.

Patanatomy. In most women with Stein-Leventhal syndrome, the ovaries retain their normal ovoid form. And only in a small part of the patients they acquire an "sausage-like" form that is not characteristic of them. In size, they exceed the ovaries of healthy women of the corresponding age: in women under 30 years, the volume of ovaries is increased by 1.5-3 times, and in patients older than this age, by 4-10 times. The largest ovaries in women with stromal tecomatosis of the ovaries. The increase is bilateral, symmetrical, rarely unilateral or asymmetric. In a small number of patients, the size of the ovaries does not exceed the norm. Their surface is smooth, pearly, often with a pronounced vascular pattern. These ovaries are distinguished by their unusual density. A variety of cystically altered follicles, 0.2 to 1 cm in diameter, is revealed on the incision. In stromal ovarian tecomatosis, the cystically altered follicles are small, numerous and arranged in the form of a necklace under the capsule. Their cavity is filled with a transparent, sometimes hemorrhagic content. The cortical layer is enlarged. The deepest layers of its yellowish color. In other cases of polycystic ovary syndrome, ovarian tissue is white marble.

Histologically, the thickening and sclerosing of the belly coat and the surface part of the cortical layer are characteristic. The thickness of the capsule can reach 500-600 nm, which is 10-15 times greater than normal. In the cortical layer, in most cases, the number of primordial follicles that is characteristic of age is preserved. There are also follicles at different stages of maturation. Cystic atresia most often undergo antral follicles. Some of the ripening follicles, as well as the cystically altered ones, also pass through the phase of fibrous atresia, but less frequently than in healthy women. The bulk of the cystic atresia follicles persist. These ovaries of patients with Stein-Leventhal syndrome primarily differ from ovaries in healthy women and from polycystic ovaries of a different etiology. The persistence of cystically altered follicles causes, along with hypertrophy of the cortical layer and thickening of the gallbladder, an increase in the mass and size of the ovaries. Cystic follicles differ in size and morphological features of their inner shell (theca externa). More than half of the patients, including stromal tecomatosis, part of the cystic-altered follicles have insufficiently differentiated theca interna, formed by fibroblast-like cells resembling the cells of the outer shell (theca externa) of the follicle. But, unlike the latter, they are somewhat enlarged, with more distinct borders. These cells are arranged with their long axis perpendicular to the cavity of the follicle, in contrast to the cells of the outer shell. Among them there are a few hypertrophied epithelioid tekalnye cells.

Another kind of inner membrane is intact, as in mature follicles, formed 3-6, sometimes by 6-8 rows of round-polygonal tecomal cells. Cystic follicles with this kind of inner membrane are most often found in patients with hyperandrogenism and adrenal origin, although in some quantity they are present in all patients.

In the process of cystic atresia, the internal current often undergoes atrophy, while it is either replaced by a hyalineized connective tissue, or by cells surrounding the ovarian stroma. Such follicles in one or another quantity are found in all patients. The pronounced hyperplasia of the inner membrane of the cystic follicles, which determines its hypertrophy, occurs only in patients with stromal ovarian tecomatosis. Such an internal current is formed by 6-8-12 rows of large epithelioid cells with a light foamy cytoplasm and large nuclei. Similar cells are arranged in columns resembling the columns of the bundle of the adrenal cortex. In ovaries with stromal tekomatosis, the hypertrophic internal current persists even in fibrous follicular atresia.

Early atresia of ripening follicles is the reason for the lack of ready-to-ovulate, resulting in yellow and white bodies are extremely rare. But if spontaneous ovulation does occur, a yellow body is formed, the reverse development of which occurs more slowly than in healthy women. Often, yellow bodies undergone by incomplete involution persist for a long time, as do white bodies. The use of clomiphene, gonadotropins, steroids and other drugs for the treatment of Stein-Levental syndrome and for the stimulation of ovulation is often accompanied by multiple ovulation and the formation of cysts of yellow bodies. Therefore, in recent years in the resected ovarian tissue of patients with Stein-Levental syndrome (polycystic ovaries), yellow bodies and / or cysts of yellow bodies are quite common. In this case, the thickened and sclerotized belly coat does not prevent ovulation.

Interstitial tissue of the ovarian cortex in Stein-Leventhal syndrome (polycystic ovaries) is more massive than in the ovaries of healthy women. Proliferative changes that cause its excessive development occur, obviously, in the early stages of the disease. Only in the ovaries with the stromal tekomatosis there is constantly increased proliferation of cells of interstitial tissue, as a result of which there is nodular or diffuse cortical stromal hyperplasia. It is this that causes a significant increase in the size of the ovaries in patients with stromal tecomatosis. They also show the transformation of cells of interstitial tissue into epithelioid cells, similar to those of the cells, and the accumulation of lipids in their cytoplasm, including free and bound cholesterol. Such polygonal cells with cytoplasm vacuolated to varying degrees are scattered singly or in nests among spindle-shaped cells of interstitial tissue, forming foci of different types of tekomatosis. The abundance of cytoplasmic lipids determines the yellowish color of the sections of the tecomatosis.

Interstitial tissue is also subjected to atrophic and sclerotic changes, which are mainly focal.

In the process of cystic atresia, the follicular epithelium degenerates and slushes, as a result of which the bulk of such follicles lacks a layer of granulosa. An exception is cystic follicles with insufficiently differentiated inner shell: they always store up to 2-3 rows of follicular cells.

According to histochemical studies, M. E. Bronstein et al. (1967, 1968), in the ovaries of patients with Stein-Leventhal syndrome the same enzymes that provide steroid biosynthesis are revealed as in the ovaries of healthy women, namely, 3-beta-hydroxysteroid dehydrogenase, NAD- and NADP-tetrazolium reductase, glucose -6-phosphate dehydrogenase, alkodehydrogenase, etc. Their activity is quite comparable with the activity of the corresponding enzymes in the ovaries of healthy women.

Thus, the hyperproduction of androgens of ovarian origin observed in the Stein-Levental syndrome (polycystic ovaries) is primarily due to the presence in the ovaries of excessive amounts of androgen-producing cells due to their persistence in cystic and fibrous follicular atresia. A significant contribution to the overproduction of androgens by ovarian tissue is made by stromal tekal cells of foci of thecocomatosis, which is also proved immunohistochemically. Sclerotic changes observed in the ovaries of patients with Stein-Leventhal syndrome (sclerosis of the gall bladder, interstitial tissue, vessel walls) are secondary. They, like the varial manifestations of the disease, are caused by hyperandrogenism and are its manifestation.