Hyperandrogenism as the cause of miscarriage

Among the hormonal disorders that lead to miscarriage, a very large place is occupied by hyperandrogenism - a pathological condition caused by changes in the secretion and metabolism of androgens. According to numerous studies, 46-77% of menstrual irregularities, 60-74% of endocrine infertility and 21-32% of miscarriages are to some extent due to hyperandrogenism. One of the severe consequences of hyperandrogenism is endocrine infertility. For miscarriage are characterized by erased "nonclassical", "late onset" forms of hyperandrogenia, which represent the greatest difficulty in identifying the source of excessive levels of androgens, assessing pathogenesis, diagnosis and management tactics.

Hyperandrogenism of adrenal origin - its "erased" forms are, according to our data, the leading factor of miscarriage in 30% of women with hyperandrogenism. The adrenal cortex consists of three zones; glomerular zone, which produces aldosterone; a cortical zone producing cortisol; a reticular zone that generates more androgens and, to a lesser extent, cortisol. In the process of metabolism, the defect of enzyme systems causes a number of disorders on the pathways of biosynthesis of hormones, which leads to the accumulation of precursors above the site of the defect of the enzyme system. Transmitted by inheritance as an autosomal recurrent trait, such defects affect various enzymes and cause their deficiency of varying severity, which causes a different severity of clinical manifestations.

The main androgenes produced by the adrenal glands are DEA, DEA-C and androstenedione. They are weak androgens, but in the body tissues, especially fatty ones, they are converted into androgens more active - testosterone and dihydrotestosterone, etc.

If the role of ACTH is clearly proved for the synthesis of cortisol and mineralocorticoids, then for the synthesis of androgens, there are still some stimulating factors besides ACTH.

The introduction of dexamethasone, which completely suppresses the production of cortisol, is not able to reduce the level of androgens below 20%, but nevertheless the secretion of androgens is suppressed by dexamethasone faster than cortisol, and is restored more quickly, despite the fact that there is no complete reduction in their level. It was found that prolactin is involved in the synthesis of androgens, but not cortisol and androstenedione.

Insulin-like growth factor, apparently, stimulates their level in plasma. Circulating steroid hormones are in plasma in a protein-related condition - corticosterone-binding globulin (CBG or transcortin), testosterone-binding globulin (TeBg), and albumin. In a free form, hormones are in a small amount.

Nonclassical, erased forms of adrenogenital syndrome begin to appear in adulthood and resemble the syndrome of polycystic ovaries, but these states need to be differentiated, since the tactics of management are different.

Androgens excreted in the urine in the form of metabolites, united in the group of 17-ketosteroids. By the level of these metabolites, one can judge the level of hyperandrogenism, but not about their source.

The adrenal source of androgens is indicated by a high level of 17a-hydroxyprogesterone and dehydroepiandrosterone-sulfate in the blood. In the diagnosis of this disorder, occurring in an erased form, there is a need for functional tests. If the 17a-hydroxyprogesterone level is above 500 ng / dl - no further testing is performed, the diagnosis is clear.

At level 17 of the SNP more than 200 ng / dl, but below 500 ng / dl, a sample with ACTH (0.25 ml ACTH (synactene depot) IV, in an hour - control) is carried out. If the 17a-hydroxyprogesterone level increases by more than 1000 ng / dl, and according to some data by 236-392%, the diagnosis of the non-classical form of adrenogenital syndrome can be determined.

Adrenogenital syndrome is an autosomal recessive disease and is inherited through 21-hydroxylase genes located on the short arm of the 6 chromosome in the HLA (major histocompatibility complex) zone. At present, the hydroxylase gene 21 is designated by the term CUR21 and its homogeneity is the pseudogen of CUR21P.

The close connection between the genes of 21-hydroxylase and the HLA system (B14.B35) makes it possible to identify possible carriers of active genes of this pathology in risk families.

It is suggested that the locus of allelic variants of 21-hydroxylase deficiency determines a different degree of deficiency, which leads to phenotypically different forms (classical, hidden or erased) of this disease.

If the 11 beta-hydroxylase enzyme, which is responsible for the transformation of 11-deoxycortizol into cortisol and deoxy-corticosterone into corticosterone, is reduced, cortisol production decreases and the level of ACTH increases and the production of deoxy-cortisol and deoxy-corticosterone, DEA and androstenedione increases.

The disease can occur in childbearing age with erased its manifestations and is characterized by hirsutism, menstrual irregularities. In the classical form, the disease is characterized by a very early onset, sometimes from the moment of birth (soltering form of adrenogenital syndrome), pronounced virilization, hypertension and is often accompanied by myopathy, retinopathy. The 11-hydroxylase gene is located on the long arm of chromosome 8, and no connection has been found with the HLA system.

In all patients, the content of androgens and deoxycortisol in plasma was increased, especially after stimulation in a sample with ACTH.

Deficiency of 3-beta-hydroxysteroid dehydrogenase is quite rare, but this enzyme takes part in the metabolism of both adrenal and ovarian and is responsible for the synthesis of progesterone from pregnenolone. In the case of a deficiency of this enzyme, the production of cortisol is disrupted, and the excess of pregnenolone is converted to dehydroepiandrosterone.

At partial defect of this system in adult women may have a slight hirsutism (DEA and DEA-C weak androgens), but there are irregularities in the menstrual cycle, reminiscent of disorders in the syndrome of polycystic ovaries.

This form of adrenogenital syndrome is observed mainly in adrenal tumors. More often the tumor affects one adrenal gland, therefore the production of cortisol and ACTH is maintained in a state of balance.

In the case of hyperplasia of the reticular cortex of the adrenal cortex or the formation of a tumor in it, which leads to atrophy of other layers of the adrenal gland, adrenogenital syndrome can be combined with Addison's disease, the primary insufficiency of the adrenal cortex. With hyperplasia of the reticular and fascicular zones, adrenogenital syndrome and Cushing syndrome develop.

However, such severe diseases for miscarriage are not characteristic.

The mechanism of abortion with erased forms of adrenogenital syndrome is caused by the violation of hormone metabolism, the presence of anovulation and the inferior second phase of the menstrual cycle, which serves as a clinical manifestation of the worn out form of adrenogenital syndrome. With the classical form of the disease, amenorrhea and infertility are observed.

In patients with habitual miscarriages with adrenal hyperandrogenism, elevated levels of 17-OP, 17KS and DEA were noted, which indicated a violation of steroidogenesis as a late-adrenogenital syndrome with 21-hydroxylase deficiency. After the dexamethasone test, a significant reduction (by 80.9%, 92%, 75.8% and 90%, respectively) of the levels of 17KS, DEA, 17-OP and cortisol was found. The inadequate increase (by 236-392%) of the concentration of cortisol, DEA, 17-OP after the ACTH test in women with unexpressed signs of hyperandrogenism and slightly altered basal level of hormones revealed latent forms of hyperandrogenism of the adrenal genesis. In 90.5% of patients in this group there was a regular biphasic menstrual cycle, not expressed hirsutism (hirsute number 9.4 ± 0.6), i.e. The clinical manifestations of hyperandrogenism were poorly expressed. 76.2% of patients had a history of habitual miscarriage, and 23.8% had secondary infertility.

Hyperandrogenia of ovarian genesis - a syndrome of polycystic ovaries was revealed only in 12.1% of those who applied to the department of miscarriage in connection with the termination of pregnancy in the anamnesis after the successful treatment of infertility.

In connection with the complicated course of pregnancy in this category of patients, we decided to stop and on this form of hyperandrogenism, although its characteristic feature is infertility, irregular menstruation up to amenorrhea, hirsutism. The main source of hyperproduction of androgens in this group of patients are the ovaries. Dysregulation of cytochrome p450c17-androgen-forming enzyme in the ovaries and adrenal glands appears to be the central pathogenetic mechanism of the development of the polycystic ovary syndrome.

The reasons for the formation of the polycystic ovary syndrome remain unclear. It is believed that this disease begins with adrenarche. During the adrenarche period, the mesencephalic cortex of the adrenal cortex stimulates (comparable to what occurs under stress), which leads to an increase in the secretion of the androgenic adrenals and, as a consequence, an increase in the formation of estrogens on the periphery (fat tissue, skin). Elevated levels of estrogen disrupt the ratio of LH / FSH, which stimulates the ovaries to produce androgens. The androgenic basis of this syndrome is shifted from the adrenal gland to the ovaries. Violation of the secretion of androgens by the adrenal cortex is observed in 50% of patients with polycystic ovary syndrome, and this combined form of hyperandrogenism is most often observed in our clinic when examining women with miscarriages and hyperandrogenia.

There are data on the inheritance of the polycystic ovary syndrome, as pathology linked to the X chromosome.

This syndrome is not associated with disorders within the hypothalamic-pituitary-ovary system. As a result of aromatization in the peripheral tissues of excessive production of androgens, the level of estrogens, mainly estrone, increases, the ratio of EVE, is violated. By the feedback mechanism, the level of FSH is inhibited and, accordingly, the level of LH increases, which leads to additional stimulation of androgens. In the presence of a high level of androgens, very early atresia of the follicles begins. Atresia of the follicles leads to a decrease in FSH and an increase in LH. In this case, there is an increase in impulse secretion of GnRH, caused by a decrease in progesterone production and dissociation of opioid-dopaminergic inhibitory effects. The elevated level of estrogen, which does not undergo cyclic changes, causes a self-sustaining state of chronic anovulation.

Approximately half of patients with hyperandrogenia of ovarian genesis have obesity. These patients often have hyperinsulinemia and insulin resistance, but this is more likely due to obesity, rather than hyperandrogenism. Insulin changes steroidogenesis regardless of the secretion of gonadotropins in the syndrome of polycystic ovaries. Insulin and insulin-like growth factor I are present in ovarian stromal cells, and a specific defect (decrease in autophosphorylation) in the binding of insulin receptors is observed in 50% of patients with polycystic ovary syndrome. In this regard, patients with polycystic ovary syndrome often develop diabetes, and during pregnancy, glucose tolerance control is necessary. Normalization of carbohydrate metabolism can be with a decrease in body weight, while the level of androgens decreases.

Diagnosis of the polycystic ovary syndrome is based on published clinical, hormonal examination and ultrasound data. According to the research, in patients with polycystic ovary syndrome the manifestations of androgenization are more pronounced: the hirsute number is 15.2 ± 0.6; increased body mass index (26.3 ± 0.8). All patients had oligomenorrhea, anovulation, a significant decrease in the generative function (in the history of primary infertility, and after an interrupted pregnancy in 64.7% - secondary infertility).

Hormonal examination revealed in all patients a high concentration of LH, T, an increase in the level of FSH. With ultrasound, a 78.6% increase in the ovaries with a characteristic pattern was noted - an increase in the volume of the ovaries, hyperplasia of the stroma, more than 10 atheretic follicles, 5 to 10 mm in size, located along the periphery under the thickened capsule.

Mixed form of hyperandrogenism - this group of patients is most heterogeneous in terms of hormones (as well as clinical parameters). Among the contingent of women with hyperandrogenism, this group was the most numerous and amounted to 57.9%. Characteristic for this group is a significant increase in the level of DEA (p <0.001) and mild hyperprolactinemia (p <0.001). Compared with hormonal parameters, in women with adrenal hyperandrogenism in patients with mixed form, there was no significant increase in 17-OP and excretion level of 17C was elevated in only 51.3% of women. A distinctive feature in the content of hormones from patients with ovarian hyperandrogenism was a moderate increase in LH with normal FSH, in 1/3 of patients the content of FSH was reduced.

The clinical picture in patients with mixed form of hyperandrogenia included symptoms characteristic of patients with adrenal and ovarian hyperandrogenia. In 49.9% of women, the menstrual cycle was broken (oligomenorrhea, amenorrhea), anovulation and infertility were noted. According to ultrasound, 46.1% of the patients in this group had ovaries and 69.2% had small-cystic changes characteristic of the polycystic ovary syndrome.

The fetal number (18.3 ± 1.0) and BMI (26.5 ± 0.7) in patients with elevated 17C level were significantly higher than those in women of this group with a normal 17C level. Most patients (96%) had EEG changes, 60.6% had changes in craniograms. In every second patient, stressful situations, injuries, and a high infectious index are noted in life.

The use of a sample with dexamvtazone and chorionic gonadotropinrevealed a mixed source of excessive androgen content: a tendency to increase in the level of 17KS, a significant increase in the content of testosterone and 17-hydroxyprogesterone following the stimulation of CG on the background of dexamethasone.

Data of medical genetic research conducted in women with hyperandrogenism showed that 14.3% of women with adrenal and mixed forms of hyperandrogenia had family forms of reproductive and hirsutism disorders. In the relatives of patients with these forms of hyperandrogenia, in comparison with population data, there is an increase in infertility 4 times, miscarriage - 10 times, violations of the menstrual cycle - 11 times and hirsutism - 14 times. In patients with ovarian form of hyperandrogenism, the genetic nature of the disease was less pronounced. However, in 50% of the patients, the pedigree was burdened by hirsutism, menstrual irregularities, spontaneous miscarriages and congenital malformations.

The complex of clinical and hormonal studies performed in patients with various forms of hyperandrogenism suffering from miscarriage of pregnancy showed that these forms, in essence, are a manifestation of clinical polymorphism of a single pathology, depending on the duration and depth of the pathological process and having as its basis a single root cause - violation hypothalamic-pituitary-adrenal-ovarian relationships at various stages of development of the female body. Significant role in the genesis of these disorders belongs to environmental factors (various diseases, infections, trauma, psycho-emotional stress, etc.), which are a trigger in the implementation of the pathological process in patients with a weighed genetic background. According to the data obtained, patients with adrenal hyperandrogenism may be referred to the initial stage of the disease. This is evidenced by the features of the clinical and hormonal status with slightly pronounced symptoms of androgenization, a high incidence of rehabilitated patients. As the disturbances in the hypothalamic-pituitary-adrenal system deepen, the ovaries are involved in the pathological process with the appearance of structural and functional disorders in them, which leads to the formation of heavier mixed forms of pathology, which present considerable difficulties in diagnosis and treatment, and extremely difficult complications in the management of pregnancy in this contingent of patients.

[1], [2], [3], [4], [5], [6], [7], [8], [9]