Hyperandrogenism as a cause of pregnancy failure

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 cycle disorders, 60-74% of endocrine infertility and 21-32% of miscarriage are caused to some extent by hyperandrogenism. One of the severe consequences of hyperandrogenism is endocrine infertility. Miscarriage is characterized by erased "non-classical", "late onset" forms of hyperandrogenism, which are the most difficult to identify the source of excess androgens, assess pathogenesis, diagnosis and management tactics.

Hyperandrogenism of adrenal genesis- its "erased" forms are, according to our data, the leading factor in miscarriage in 30% of women with hyperandrogenism. The adrenal cortex consists of three zones: the zona glomerulosa, which produces aldosterone; the zona fasciculata, which produces cortisol; the zona reticularis, which produces androgens to a greater extent and cortisol to a lesser extent. In the process of metabolism, the defect of the enzyme systems causes a number of disturbances in the pathways of hormone biosynthesis, which leads to the accumulation of precursors above the site of the enzyme system defect. Transmitted by inheritance as an autosomal recessive trait, such defects affect various enzymes and cause their deficiency of varying severity, which determines the different severity of clinical manifestations.

The main androgens produced by the adrenal glands are DHEA, DHEA-S and androstenedione. They are weak androgens, but in the body tissues, especially in fat, they are converted into more active androgens - testosterone and dihydrotestosterone, etc.

If the role of ACTH in the synthesis of cortisol and mineralocorticoids is clearly proven, then for the synthesis of androgens, some other stimulating factors in addition to ACTH are necessary.

The administration of dexamethasone, which completely suppresses cortisol production, is unable to reduce androgen levels below 20%, but nevertheless androgen secretion is suppressed by dexamethasone faster than cortisol, and is restored faster, despite the fact that their level is not completely reduced. It was found that prolactin is involved in the synthesis of androgens, but not cortisol and androstenedione.

Insulin-like growth factor appears to stimulate their plasma levels. Circulating steroid hormones are found in plasma bound to proteins - corticosterone-binding globulin (CBG or transcortin), testosterone-binding globulin (TeBg) and albumin. Free hormones are present in small quantities.

Non-classical, latent forms of adrenogenital syndrome begin to manifest in adulthood and resemble polycystic ovary syndrome, but these conditions must be differentiated, since the management tactics are different.

Androgens are excreted in urine as metabolites, which are grouped into 17-ketosteroids. The level of these metabolites can be used to judge the level of hyperandrogenism, but not their source.

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

If the level of 17 ONP is more than 200 ng/dl, but less than 500 ng/dl, an ACTH test is performed (0.25 ml ACTH (Synacthen-depot) intravenously, after an hour - control). If the level of 17a-hydroxyprogesterone increases by more than 1000 ng/dl, and according to some data by 236-392%, then the diagnosis of the non-classical form of adrenogenital syndrome can be determined.

Adrenogenital syndrome is an autosomal recessive disease and is inherited through the 21-hydroxylase genes located on the short arm of chromosome 6 in the HLA (major histocompatibility complex) zone. Currently, the 21-hydroxylase gene is designated by the term CYP21 and its homogene is the pseudogene CYP21P.

The close relationship between the 21-hydroxylase genes and the HLA system (B14.B35) allows us to identify possible carriers of active genes for this pathology in families at risk.

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

When 11 beta-hydroxylase is impaired, an enzyme responsible for converting 11-deoxycortisol into cortisol and deoxycorticosterone into corticosterone, the production of cortisol decreases and the level of ACTH increases in compensation, and the production of deoxycortisol and deoxycorticosterone, DHEA and androstenedione increases.

The disease may manifest itself in childbearing age with its manifestations erased and is characterized by hirsutism, menstrual disorders. In the classical form, the disease is characterized by a very early onset, sometimes from the moment of birth (salt-wasting 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 with the HLA system has been identified.

All patients had elevated plasma androgen and deoxycortisol levels, especially after stimulation with ACTH.

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

With a partial defect of this system, adult women may have slight hirsutism (DHEA and DHEA-S are weak androgens), but there are menstrual cycle disorders reminiscent of those in polycystic ovary syndrome.

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

In the case of development of hyperplasia of the reticular zone of the adrenal cortex or 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 - primary insufficiency of the adrenal cortex. With hyperplasia of the reticular and fascicular zones, adrenogenital syndrome and Cushing's syndrome develop.

However, such severe diseases are not typical for miscarriage.

The mechanism of pregnancy termination in latent forms of adrenogenital syndrome is caused by disruption of hormone metabolism processes, the presence of anovulation and an incomplete second phase of the menstrual cycle, which serves as a clinical manifestation of the latent form of adrenogenital syndrome. In the classical form of the disease, amenorrhea and infertility are observed.

In patients with habitual miscarriage with adrenal hyperandrogenism, elevated levels of 17-OP, 17KS, and DHEA were observed, indicating impaired steroidogenesis similar to late-onset adrenogenital syndrome with 21-hydroxylase deficiency. After the dexamethasone test, a significant decrease (by 80.9%, 92%, 75.8%, and 90%, respectively) in the levels of 17KS, DHEA, 17-OP, and cortisol was revealed. An inadequate increase (by 236-392%) in the concentration of cortisol, DHEA, and 17-OP after the ACTH test in women with mild signs of hyperandrogenism and slightly altered basal hormone levels revealed hidden forms of adrenal hyperandrogenism. 90.5% of patients in this group had a regular two-phase menstrual cycle, mild hirsutism (hirsutism number 9.4±0.6), i.e. clinical manifestations of hyperandrogenism were weakly expressed. 76.2% of patients had a history of habitual miscarriage, and 23.8% had secondary infertility.

Hyperandrogenism of ovarian genesis - polycystic ovary syndrome was detected only in 12.1% of those who applied to the miscarriage department due to a history of termination of pregnancy after successful infertility treatment.

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

The causes of polycystic ovary syndrome remain unclear. It is believed that this disease begins with adrenarche. During adrenarche, the reticular zone of the adrenal cortex is stimulated (comparable to what occurs during stress), which leads to increased secretion of androgens by the adrenal glands and, as a consequence, increased formation of estrogens in the periphery (adipose tissue, skin). Increased estrogen levels disrupt the LH/FSH ratio, which stimulates the ovaries to produce androgens. The androgenic basis of this syndrome shifts from the adrenal glands to the ovaries. Impaired androgen secretion 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 miscarriage and hyperandrogenism.

There is evidence of the inheritance of polycystic ovary syndrome as an X-linked pathology.

This syndrome is not associated with disturbances within the hypothalamic-pituitary-ovarian system. As a result of aromatization of excess androgen production in peripheral tissues, the level of estrogens, mainly estrone, increases, the EVE ratio is disturbed. According to 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 high androgen levels, follicular atresia begins very early. Follicular atresia leads to a decrease in FSH and an increase in LH. At the same time, there is an increase in the pulse secretion of GnRH, caused by a decrease in progesterone production and dissociation of opioid-dopaminergic inhibitory effects. The elevated level of estrogens, which is not subject to cyclic changes, causes a self-sustaining state of chronic anovulation.

Approximately half of patients with ovarian hyperandrogenism are obese. These patients often have hyperinsulinemia and insulin resistance, but this is more likely due to obesity than hyperandrogenism. Insulin alters steroidogenesis regardless of gonadotropin secretion in polycystic ovary syndrome. Insulin and insulin-like growth factor I are present in ovarian stromal cells, and a specific defect (decreased autophosphorylation) in binding to insulin receptors is observed in 50% of patients with polycystic ovary syndrome. In this regard, patients with polycystic ovary syndrome often develop diabetes, and glucose tolerance must be monitored during pregnancy. Normalization of carbohydrate metabolism can be achieved by weight loss, which also reduces androgen levels.

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

Hormonal examination revealed high concentration of LH, T, increased FSH level in all patients. Ultrasound examination revealed enlarged ovaries in 78.6% with a characteristic picture - increased ovarian volume, stromal hyperplasia, more than 10 atretic follicles, 5 to 10 mm in size, located on the periphery under a thickened capsule.

Mixed hyperandrogenism - this group of patients is the most heterogeneous in terms of hormone content (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 reliable increase in the level of DHEA (p < 0.001) and moderate hyperprolactinemia (p < 0.001). Compared with the hormonal parameters in women with adrenal hyperandrogenism, patients with the mixed form did not have a reliable increase in 17-OP and the excretion level of 17KS was increased only in 51.3% of women. A distinctive feature in terms of hormone content from patients with ovarian hyperandrogenism was a moderate increase in LH with normal FSH values; in 1/3 of patients, the FSH content was reduced.

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

The hirsute number (18.3 ± 1.0) and BMI (26.5 ± 0.7) in patients with elevated 17KS levels were significantly higher than those in women of this group with normal 17KS levels. Most patients (96%) had EEG changes, 60.6% had changes in craniograms. Every second patient had stressful situations, injuries, and a high infectious index in their lives.

Use of the dexamvtasone and human chorionic gonadotropin testallowed us to identify a mixed source of excess androgen content: a tendency towards an increase in the level of 17KS, a reliable increase in the content of testosterone and 17-hydroxyprogesterone after stimulation with hCG while taking dexamethasone.

The data of the medical-genetic study conducted in women with hyperandrogenism showed that 14.3% of women with adrenal and mixed forms of hyperandrogenism had familial forms of reproductive dysfunction and hirsutism. In the relatives of patients with these forms of hyperandrogenism, compared with the population data, the incidence of infertility was 4 times higher, miscarriages were 10 times higher, menstrual cycle disorders were 11 times higher, and hirsutism was 14 times higher. In patients with the ovarian form of hyperandrogenism, the genetic nature of the disease was less pronounced. At the same time, 50% of patients had a family history of hirsutism, menstrual cycle disorders, spontaneous abortions, and congenital malformations.

A set of clinical and hormonal studies conducted in patients with various forms of hyperandrogenism suffering from miscarriage showed that these forms are essentially a manifestation of clinical polymorphism of a single pathology depending on the duration and depth of the pathological process and having a single root cause - a violation of the hypothalamic-pituitary-adrenal-ovarian relationships at various stages of development of the female body. A significant role in the genesis of these disorders belongs to environmental factors (various diseases, infections, injuries, psycho-emotional stress, etc.), which are a trigger in the implementation of the pathological process in patients with an aggravated genetic background. According to the data obtained, patients with adrenal hyperandrogenism can be attributed to the initial stage of the disease. This is evidenced by the features of the clinical and hormonal status with slightly expressed symptoms of androgenization, a high frequency of rehabilitated patients. As the disturbances in the hypothalamus-pituitary-adrenal system deepen, the ovaries become involved in the pathological process, with the emergence of structural and functional disturbances in them, which leads to the formation of more severe mixed forms of pathology, which present significant difficulties in diagnosis and treatment, and extremely great difficulties in managing pregnancy in this group of patients.

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