Causes and pathogenesis of polycystic ovaries

The cause and pathogenesis of polycystic ovary syndrome are unknown. The early idea of the leading role of tunica albuginea sclerosis in the pathogenesis, which impedes ovulation, has been rejected, since its severity has been shown to be an androgen-dependent symptom.

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

In the 1960s, a number of researchers conducted work on studying steroidogenesis in ovarian tissue in vitro. When incubating ovarian sections of polycystic ovaries with labeled A, V. B. Mahesh and R. B. Greenblatt discovered excessive accumulation of dehydropyandrosterone (DHEA). When A was added to the incubate, it was quickly converted into estrogens, and after adding chorionic gonadotropin, the DHEA level increased.

GF Erickson showed that in both polycystic ovaries and normal ovaries, excess formation of testosterone (T) and androgens (A) occurs in small maturing follicles that have not reached 6 mm in diameter, since in these follicles the granulosa cells have not yet reached maturity and aromatase activity has not manifested. According to Falk's bicellular theory, estrogens are synthesized in two stages in two groups of cells: in theca interna folliculi, synthesis is carried out mainly to the level of 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 quantities. The aromatase activity of granulosa cells is under the control of pituitary FSH. In addition, K. Savard, B. F. Rice showed that both in healthy and polycystic ovaries, testosterone is a unique product of the stroma, and in 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 can be peripheral metabolism.

Most researchers find elevated levels of luteinizing hormone, absence of its ovulatory peak, normal or decreased levels of FSH in polycystic ovary syndrome. In this case, the LH/FSH ratio is always disturbed towards the predominance of luteinizing hormone. Disturbance of gonadotropic regulation is not limited to the level of the hypothalamic-pituitary system. A. D. Dobracheva revealed disturbance of intra-ovarian interaction of luteinizing hormone with the receptor, i.e., at the first stage of gonadotropic regulation. A correlation was found between the level of ovarian T and the features of binding of labeled luteinizing hormone in the interstitial tissue of the ovaries. However, elevated levels of LH may not be associated with primary hypothalamic disorders, but are caused by primary hyperandrogenism.

Thus, it is not hyperandrogenism itself that leads to an increase in the level of luteinizing hormone, but an 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 LH-RH, which results in increased secretion of luteinizing hormone.

The ovulatory peak of the latter is absent. Sensitization of the pituitary gland to LH-RH is confirmed by a test with luteinizing hormone 100 mcg intravenously, which reveals a hyperergic response of luteinizing hormone, but not FSH. High levels of luteinizing hormone cause hyperplasia of the ovarian stroma, which leads to increased synthesis of ovarian androgens. In addition, the theca interna folliculi in conditions of anovulation and insufficient maturity of granulosa cells is also a source of androgens.

The mechanism may be initiated 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. Increased androgen levels may lead to an increase in estraglandular estrogen production, which in turn will cause an increase in LH/FSH. The androgenic basis of this syndrome then shifts from the adrenal to the ovarian.

The role of the adrenal glands in the pathogenesis of polycystic ovary syndrome is not limited to the adrenarche period. Numerous attempts to clearly differentiate the adrenal and ovarian contribution of androgens using suppression and stimulation tests, selective catheterization of the ovarian and adrenal veins have not yielded any results. Approximately 20% of patients with polycystic ovary syndrome have an increased level of 17-KS excretion, but it should be emphasized that this indicator mainly reflects the content of DHEA and A, and not testosterone.

DHEA and its sulfate are the main adrenal androgens. Their suppression by dexamethasone in patients with polycystic ovary syndrome indicates adrenal genesis of hyperandrogenism. Levels of T (testosterone), A and 17-OH-progesterone are weakly suppressed by dexamethasone, which indicates their ovarian origin. These studies suggest, but do not establish exactly, that hyperandrogenism in patients with polycystic ovary syndrome is mixed - adrenal and ovarian. In some patients with polycystic ovary syndrome, adrenal hyperplasia was detected. M. L. Leventhal indicates that significant secretion of androgens by 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 ACTH stimulation. Many authors conclude that combined hyperandrogenism - ovarian and adrenal - occurs in polycystic ovary syndrome.

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

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

Thyroid hormones are the only hormones, other than E2, that stimulate the production of TESG.

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

As SS C. Yen pointed out, there were reports that the syndrome may manifest as a disease inherited in a dominant manner and linked to the X chromosome. In some patients, the disappearance of the long arm of the X chromosome, mosaicism, was noted. However, most patients with polycystic ovary syndrome have a normal karyotype of 46/XX.

Of particular interest is the subgroup of patients with polycystic ovary syndrome in families with ovarian hyperthecosis (thecomatosis), which is often difficult to distinguish clinically from polycystic ovary syndrome. Familial forms of this disease indicate genetic disorders. At the same time, the role of insulin in the pathogenesis of thecomatosis has been identified in recent years. RL Barbieri showed that there is a close relationship between hyperandrogenism and hyperinsulinemia. Insulin may be involved in ovarian steroidogenesis in humans. In incubates of ovarian stroma from healthy women, LH plus insulin acted as agonists, stimulating the production of A and T.

Pathological anatomy. In most women with Stein-Leventhal syndrome, the ovaries retain their normal ovoid shape. Only in a small number of patients do they acquire an unusual "sausage-shaped" shape. They are larger than the ovaries of healthy women of the same age: in women under 30, the ovarian volume is increased by 1.5-3 times, and in patients older than this age - by 4-10 times. The largest ovaries are in women with stromal ovarian thecomatosis. The enlargement is bilateral, symmetrical, rarely unilateral or asymmetrical. In a small number of patients, the ovaries do not exceed the norm in size. Their surface is smooth, pearlescent, often with a pronounced vascular pattern. These ovaries are distinguished by their unusual density. The section reveals a variable number of cystically altered follicles, with a diameter of 0.2 to 1 cm. In stromal ovarian thecomatosis, the cystically altered follicles are small, numerous, and arranged in the form of a necklace under the capsule. Their cavity is filled with transparent, sometimes hemorrhagic contents. The cortex is expanded. Its deepest layers are yellowish. In other cases of polycystic ovary syndrome, the ovarian tissue is white marble.

Histologically, thickening and sclerosis of the protein shell and the superficial part of the cortex are characteristic. The thickness of the capsule can reach 500-600 nm, which is 10-15 times greater than normal. In the cortex, in most cases, the number of primordial follicles characteristic of age is preserved. Follicles at different stages of maturation are also encountered. Antral follicles are most often subject to cystic atresia. Some maturing follicles, like cystically altered ones, also undergo a phase of fibrous atresia, but less often than in healthy women. The majority of cystically atretic follicles persist. This is how the ovaries of patients with Stein-Leventhal syndrome differ primarily from the ovaries of healthy women and from polycystic ovaries of other etiologies. The persistence of cystic follicles causes, along with hypertrophy of the cortex and thickening of the protein coat, an increase in the mass and size of the ovaries. Cystic follicles differ in size and morphological features of their inner shell (theca externa). In more than half of patients, including those with stromal thecomatosis, some of the cystic follicles have insufficiently differentiated theca interna, formed by fibroblast-like cells resembling the cells of the outer shell (theca externa) of the follicle. However, unlike the latter, they are somewhat enlarged, with clearer boundaries. These cells are located with their long axis perpendicular to the cavity of the follicle, unlike the cells of the outer shell. Among them, there are a few hypertrophied epithelioid thecal cells.

Another type of inner shell is intact, as in mature follicles, formed by 3-6, sometimes 6-8 rows of round-polygonal thecal cells. Cystic follicles with this type of inner shell are most often found in patients with hyperandrogenism of adrenal origin, although they are present in varying quantities in all patients.

In the process of cystic atresia, the internal theca often undergoes atrophy, and is either replaced by hyalinized connective tissue or by cells of the surrounding ovarian "stroma". Such follicles are found in varying quantities in all patients. Marked hyperplasia of the internal lining of cystic follicles, causing its hypertrophy, occurs only in patients with stromal thecomatosis of the ovaries. Such internal theca is formed by 6-8-12 rows of large epithelioid cells with light foamy cytoplasm and large nuclei. Such cells are arranged in columns resembling the columns of the fascicular zona of the adrenal cortex. In ovaries with stromal thecomatosis, hypertrophied internal theca persists even in fibrous atresia of the follicles.

Early atresia of maturing follicles is the reason for the absence of those ready for ovulation, as a result, corpora lutea and corpora alba are extremely rare. But if spontaneous ovulation does occur, a corpus luteum is formed, the reverse development of which occurs more slowly than in healthy women. Often, corpora lutea that have undergone incomplete involution persist for a long time, as do corpora alba. The use of clomiphene, gonadotropins, steroids and other drugs for the treatment of Stein-Leventhal syndrome and for ovulation stimulation is often accompanied by multiple ovulation and the formation of corpora lutea cysts. Therefore, in recent years, corpora lutea and/or corpora lutea cysts have been found quite often in the resected ovarian tissue of patients with Stein-Leventhal syndrome (polycystic ovaries). In this case, the thickened and sclerosed protein shell does not interfere with ovulation.

The 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 apparently occur at the early stages of the disease. Only in ovaries with stromal thecomatosis is there a constant increased proliferation of interstitial tissue cells, resulting in nodular or diffuse cortical stromal hyperplasia. It is this that causes a significant increase in the size of the ovaries in patients with stromal thecomatosis. They also show transformation of interstitial tissue cells into epithelioid ones, similar to thecal cells, and accumulation of lipids in their cytoplasm, including cholesterol in free and bound form. Such polygonal cells with cytoplasm vacuolated to varying degrees are scattered singly or in nests among the spindle-shaped cells of the interstitial tissue, forming foci of thecomatosis of varying sizes. The abundance of cytoplasmic lipids causes the yellowish color of the areas of thecomatosis.

The interstitial tissue is also subject to atrophic and sclerotic changes, which are mainly focal in nature.

In the process of cystic atresia, the follicular epithelium degenerates and exfoliates, as a result of which the majority of such follicles are deprived of the granulosa layer. The exception is cystic follicles with an insufficiently differentiated inner membrane: they always retain up to 2-3 rows of follicular cells.

According to histochemical studies by M. E. Bronstein et al. (1967, 1968), the same enzymes that ensure the biosynthesis of steroids are found in the ovaries of patients with Stein-Leventhal syndrome as in the ovaries of healthy women, namely 3-beta-oxysteroid dehydrogenase, NAD- and NADP-tetrazolium reductases, glucose-6-phosphate dehydrogenase, alkyl dehydrogenase, 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 Stein-Leventhal syndrome (polycystic ovaries) is caused primarily by the presence of excess androgen-producing cells in the ovaries due to their persistence in cystic and fibrous atresia of the follicles. Stromal thecal cells of thecomatosis foci make a significant contribution to the hyperproduction of androgens by ovarian tissue, which has also been proven immunohistochemically. Sclerotic changes observed in the ovaries of patients with Stein-Leventhal syndrome (sclerosis of the tunica albuginea, interstitial tissue, vascular walls) are secondary. They, like the varicose manifestations of the disease, are caused by hyperandrogenism and are its manifestation.