Mild hyperandrogenism. Symptoms and treatment of ovarian hyperandrogenism. Congenital adrenal hyperandrogenism

Content

Ovarian hyperandrogenism is a common endocrine pathology. This condition is diagnosed by gynecologists in 4-5% of patients. It occurs if in the female body, male sex hormones begin to be produced in excess by the ovaries.

Varieties and causes of the syndrome

Gynecologists distinguish hyperandrogenism of adrenal, ovarian and mixed genesis. Pathology can be hereditary or acquired. It is primary and secondary.

Most often, ovarian hyperandrogenism occurs with such diseases:

• primary polycystic ovaries, which is formed in adolescent girls;
• polycystic ovary syndrome (secondary polycystic);
• hyperthecosis, causes hyperandrogenic symptoms in postmenopausal women.

Hyperandrogenism occurs when an excessive amount of androgens is produced in the body or their increased formation from the precursors of androgenic hormones is observed. The specified diagnosis is also established if, against the background of a normal concentration of androgens, the susceptibility of target tissues to them increases.

Attention! In rare cases, pathology occurs due to the fact that in the body of a woman the level of globulins, which are needed to bind sex hormones, is lowered.

Globulins are necessary to prevent the interaction of androgens and specific receptors. Signs of androgenism may appear with ovarian tumors. There are certain forms of cancer in which androgen hypersecretion is observed.

Symptoms of hyperandrogenism in women

Hyperandrogenism in patients is accompanied by an extensive list of gynecological, cosmetic and dysmetabolic signs. You can suspect the development of pathology by the following symptoms:

• violation of the regularity of the menstrual cycle;
• amenorrhea;
• anovulatory menstrual cycles;
• damage to the skin, most often women complain of acne, dry skin with flaky areas, seborrhea, alopecia;
• hirustism (increased male pattern hair growth);
• the appearance of excess weight;
• impaired glucose tolerance;
• amyotrophy;
• coarsening of the voice.

With congenital hyperandrogenism, anomalies in the development of the genital organs are observed. During a gynecological examination, the doctor may reveal clitoral hypertrophy, partial fusion of the urogenital sinus, and labia majora.

Most often, pathology is detected when women turn to a gynecologist about infertility. Some have mild hyperandrogenism of ovarian origin. In this case, there may be no external changes, and the level of androgens in the blood is within the normal range. To clarify the diagnosis, the patient is assigned a comprehensive medical examination.

Diagnostics

To establish a diagnosis, a gynecologist:

• collects anamnesis;
• conducts examination and two-hand examination;
• prescribes ultrasound diagnostics;
• gives directions for blood and urine tests.

The patient needs to determine the concentration of steroid hormones in the body. It is recommended to pass tests to determine the level:

• testosterone (total, free);
• DHEA-S;
• GSPS.

With hyperandrogenism of ovarian genesis, an increase in ASD and testosterone is observed. An excessively high level of total testosterone or DHEA-S may indicate the development of a tumor that synthesizes androgens.

With polycystic ovary syndrome, you need to not only look at the content of male hormones, but also check the overall hormonal background. Pathology is accompanied by:

• balancing the content of testosterone and luteinizing hormone;
• a decrease in the content of follicle-stimulating hormone;
• an increase in the concentration of prolactin.

With the disease, an increase in blood glucose is observed. The diagnosis can only be established by an experienced gynecologist, taking into account the examination data, instrumental examination, information from the collected patient history and test results.

Treatment Methods

The selection of therapy tactics should be carried out by the attending gynecologist, taking into account the underlying disease, which led to the development of hyperandrogenic syndrome.

With polycystic ovaries, hormonal therapy is selected. Patients with hirustisoma may be prescribed Medroxyprogesterone, Spironolactone. If necessary, patients are selected oral contraceptives that have an antiandrogenic effect. Often gynecologists prescribe Diana-35. Under the influence of hormonal pills, the process of ovulation, the production of gonadotropins is inhibited, and the production of ovarian hormones is suppressed. As a result, androgen receptors are blocked, testosterone and SHPS do not rise.

Patients who developed hyperandrogenism during the postmenopausal period are prescribed Klimen. If androgen-secreting malignant tumors of the ovaries are detected, the treatment should be selected by a gynecologist-oncologist. Most patients are prescribed surgical treatment, chemopreventive and radiation therapy. With the appearance of benign neoplasms that produce androgens, surgical removal is indicated.

Attention! Overweight women are prescribed diet and exercise. Weight loss contributes to the normalization of hormonal levels.

Forecast

Many women, with the right treatment tactics, manage to stop hyperandrogenism of ovarian origin. With polycystic ovaries, good results are observed with conservative therapy. Properly selected treatment allows you to restore ovulation, normalize the regularity of the menstrual cycle. If conservative therapy is ineffective, electrocoagulation of the ovaries is prescribed.

In the treatment of hyperandrogenism, not only the work of the reproductive organs is normalized, but also cosmetic defects are reduced. They can also be eliminated with the help of cosmetic manipulations. But they will be effective provided that the woman is undergoing treatment aimed at getting rid of the underlying pathology.

Ovarian hyperandrogenism occurs in patients with hormonal disorders that have arisen against the background of polycystic ovaries, tumors or hyperthecosis. Treatment should be selected by a gynecologist after a full examination of the patient and clarification of the cause that provoked the appearance of hyperandrogenic symptoms. You can find out how androgenism manifests itself, what tests are needed to establish a diagnosis, how treatment is carried out, you can from the video

Hyperandrogenism of adrenal origin is a special pathological condition in which the hormonal status of a woman changes dramatically. Androgens are male hormones. If they are produced in large quantities in a woman's body, the appearance and basic physiological processes change.

Hyperandrogenism in patients is manifested by masculine traits. Many scientists are still concerned about the question of how to get rid of these problems forever, what it is, which causes hypertrophy. In the segment of diseases of endocrine origin, which are considered by gynecological specialists, the primacy belongs to pathological conditions caused by thyroid dysfunction and hyperandrogenism.

Adrenal hyperandrogenism is a pathology leading to a total hormonal imbalance in women, amenorrhea and subsequent infertility. The close relationship between the ovaries and adrenal glands is based on hormonal interaction and the influence of all hormonal substances on the functioning of organs and systems of the whole body. Normally, follicles are surrounded by special cellular structures. If there are too many androgens in the female body, normal follicular growth is impossible.

Pathology may not appear for some time. However, over time, overgrowth (atresia) of follicular structures leads to polycystic ovaries. A lot of cystic formations are formed on the gland, which will directly negatively affect the health of a woman. The main causes of polycystic ovary syndrome are heavy loads and an excess of male hormones.

Hyperandrogenism of ovarian origin, according to scientists, can develop due to the following adverse circumstances:

• Dysfunction of the pituitary gland or hypothalamus (in this case, the level of LH rises, causing a total hormonal imbalance);
• Polycystic ovary syndrome is a consequence of the malfunction of the adrenal glands precisely in the prepubertal period. The glands produced too many androgens, the reasons for this particular dysfunction are still not clear;
• Overweight;
• Hyperthecosis;
• Leydigoma;
• Congenital hyperplasia of the adrenal cortex;
• insulin resistance;
• Hyperinsulinemia;
• Androgen-secreting tumors of the ovaries and adrenal glands (these neoplasms are able to form a vivid picture of the clinical signs characteristic of hyperadrogenism);
• Hypothyroidism of the primary type.

Ovarian hyperplasia

It is worth considering separately the hyperplasia of the ovaries, as one of the key factors leading to the development of hyperandrogenism. Stromal ovarian hyperplasia and hyperthecosis - bilateral growth of the ovarian stroma. The pathological process is based on the mechanisms of proliferation and luteinization. Clinically, hyperplasia processes in combination with progressive hyperadrogenism resemble Cushing's syndrome in its "classic" form, extensive ovarian androblastoma, or scleropolycystosis of ovarian formations.

Features of the development of hyperandrogenism in women

The state of hyperadrenogeny for a woman's body is the most difficult test. The “purely female” reasons for the development of such a powerful imbalance are considered to be the following conditions:

1. Various forms of adrenogenital syndrome in women (male sex hormones are not transformed into glucocorticoid substances, but into androgens, accumulating in the body more and more every day);
2. The presence of tumors in the adrenal glands or ovaries, which increase the number of cell formations that secrete androgens (irreversible infertility occurs, reproductive technologies are not used in such a case, focusing all efforts on saving the patient's life);
3. Pathologies of other organs of the endocrine system, indirectly leading to the development of hyperandrogenism (menstrual and reproductive functions, as a rule, suffer less than other important physiological aspects of a woman's health).

Often, excessive synthesis of androgens by the glandular structures of a woman's body is identified with Stein-Leventhal syndrome, against the background of hypothalamic syndrome, with hyperlactinemia. The main complaints of women are a sharp deterioration in appearance and well-being: no onset of ovulation with suppression of estrogen synthesis, the appearance of hypertrichosis, acne. A woman looks "like a man", and the reproductive system is physiologically depressed.

Symptoms

Adrenal hyperandrogenism in most women is manifested by a whole galaxy of specific symptoms. All clinical signs are conventionally divided into two categories: major and minor.

Main symptoms:

1. Excessive hairiness of the skin. Hair growth is primarily observed in the abdomen (especially in the lower segment), chest, upper and lower extremities. The most severe form - hirsutism - coarse hair begins to grow on the cheeks of women;
2. The appearance of characteristic bald patches on the head (alopecia of adrenal origin in women);
3. Strong changes in the state of the dermal tissue (form acne, acne, pimples, peeling, inflammatory reactions). An important nuance is that any manipulations by the cosmetologist do not give any results, since the reason lies deep inside;
4. Muscular atrophy;
5. The rapid development of osteoporosis.

The syndrome of hyperandrogenism can form a variety of pathological processes: hypertrophy of the adrenal glands, injuries of the hypothalamus, dysfunction of any gland in the body, and much more. Depending on what causes the disease, how much they affected the patient, and the course of the disease and the presence of secondary symptoms will depend. Women may suffer from such abnormal phenomena and pathological conditions:

1. Sharp weight gain;
2. The formation of the genital organs according to the intermediate type;
3. Anomalies of the menstrual cycle;
4. Infertility (less often - miscarriage, since it is generally difficult for a woman to become pregnant);
5. Sharp jumps in blood pressure;
6. seborrhea;
7. Baryphony (sharp coarsening and lowering the tone of the voice).

Women are prone to depression. They catch colds more often, get tired faster.

Diagnostic measures

At the very beginning, the doctor should conduct a differential diagnosis, excluding other specific diseases. We are talking about the following pathologies:

1. Acromegaly;
2. Liver ailments;
3. Abnormal sex differentiation;
4. Cushing's syndrome;
5. Tumors of the adrenal glands capable of secreting androgens.

The diagnosis of adrenal hyperandrogenism can only be made after all proper diagnostic procedures have been performed. First of all, the patient is prescribed the following tests:

1. The study of the hormonal background. Modern methods of examination in the laboratory allow you to accurately determine the amount of prolactin, free and total testosterone, FSH levels in the blood. Due to the fact that hormonal substances are produced unevenly during the day, samples are taken three times a day;
2. Identification of ketosteroids in urine;
3. Markers on HG.

Uncontrolled and uncontrolled hypertension is a disease of adrenal origin, therefore, analyzes and studies traditional for identifying GB pathologies are also relevant. The patient is required to prescribe an intravaginal ultrasound examination; diagnosis using MRI or CT is relevant if the characteristics of the patient's body need to be studied in great detail. In order to accurately establish the type and characteristics of the course of the disease, ultrasound type diagnostics can be performed several times.

Treatment of adrenal hyperandrogenism

Adrenal hyperandrogenism is difficult to treat. This is due to the fact that the disease itself is extremely unstable in terms of severe symptoms, and is also formed on the basis of other pathological conditions, which are no less serious in their severity.

Therapy in women is always carried out according to an individual plan. First of all, when developing a treatment plan, the doctor should also be guided by some of the wishes of the woman. The following aspects play an important role:

1. Desire to have children in the future;
2. No need to maintain fertile functionality;
3. The need to protect the organs of the reproductive system from possible complications (for example, a burdened history and the risk of getting cancer).

Hyperandrogenism, the treatment of which lasts for years, will disturb the woman for a long time with her "classic" symptoms. Restoring your "healthy" appearance can be very difficult. It is important to adhere to all treatment rules, the symptoms in this case may not disappear immediately, but the problems will definitely not worsen.

Women will have to take drugs containing the required amount of hormones for a long time, which will correct the hormonal status of the patient. During treatment, doctors control ketosteroids excreted in urine.

Surgical treatment of the disease is carried out using the following techniques:

1. Wedge-shaped resection of the ovaries;
2. Demedication of glands with notch (sometimes without notch) of follicular cysts;
3. electrocautery;
4. Thermal cauterization.

The choice of technique is laid on the shoulders of the attending physician, who must take into account all the characteristics of the patient's body and the specifics of her illness. After surgery, in any case, long-term hormone therapy will be required.

In general, the disease is complex, rather specific. It is difficult for patients to live with the disease, both physically and psychologically. Moreover, long-term hormonal treatment regimens can also adversely affect a woman's condition. Each case is individual and requires a competent approach, careful acquaintance and specially thought-out schemes of therapeutic effects on the patient.

For citation: Pischulin A.A., Karpova E.A. Ovarian hyperandrogenism and metabolic syndrome // BC. 2001. No. 2. S. 93

Endocrinological Research Center of the Russian Academy of Medical Sciences, Moscow

FROM the syndrome of ovarian hyperandrogenism of non-tumor origin or hyperandrogenic ovarian dysfunction, previously called Stein-Leventhal syndrome, is currently, according to the WHO classification, better known in the world literature as polycystic ovary syndrome (SPY).

The clinical picture of PCOS is manifested by a chronic anovulatory state of the ovaries or severe hypofunction of the corpus luteum, which leads to a bilateral increase in the size of the ovaries with thickening and sclerosis of the albuginea. These changes are manifested by a violation of the menstrual function - opsomenorrhea, amenorrhea, but the development of metrorrhagia is not excluded. Violations of folliculogenesis lead to the development of anovulatory primary or secondary infertility.

One of the main diagnostic criteria for PCOS is hyperandrogenemia. - an increase in the level of androgenic steroids in the blood (such as testosterone, androstenedione), which leads to the development of hirsutism and other androgen-dependent dermopathies.

Obesity or overweight often accompanies PCOS. Determination of body mass index (BMI) allows you to identify the degree of obesity. Measurement of indicators of waist (WT) and hips (HB) and their ratio indicates the type of obesity (abdominal type of obesity is unfavorable prognostically, in which WT/HB > 0.85).

In addition to the main symptoms of the disease, the clinical picture is largely determined by general metabolic disorders, such as dyslipidemia, impaired carbohydrate metabolism, and an increased risk of developing hyperplastic and tumor processes in the genitals. Dyslipidemia is an increase in triglycerides, cholesterol, low density lipoprotein, very low density lipoprotein and a decrease in high density lipoprotein. These disorders lead to the risk of early development of atherosclerotic vascular changes, hypertension and coronary heart disease.

Carbohydrate metabolism disorders consist in the development of the insulin resistance-hyperinsulinemia complex, which has recently been the main direction in the study of the pathogenetic links in the development of PCOS.

In the 60s, the pathogenesis of PCOS was associated with a primary enzymatic defect in ovarian 19-hydroxylase and/or 3b-dehydrogenase, combining these disorders under the concept of primary polycystic ovaries. However, in the works of subsequent years, it was shown that the aromatase activity of granulosa cells is an FSH-dependent function.

An increased level of luteinizing hormone (LH), the absence of its ovulatory peak, a normal or reduced level of follicle-stimulating hormone (FSH) with an impaired LH/FSH ratio (2.5-3) detected in PCOS suggested a primary violation of gonadotropic regulation of steroidogenesis in the ovarian tissue with the development of a secondary polycystic ovaries.

Until the mid-1980s, it was believed (the theory of S.S.C. Yen) that the trigger mechanism in the pathogenesis of PCOS is the excessive synthesis of androgens by the adrenal glands during the adrenarche period as a result of an altered sensitivity of the adrenal glands to ACTH or excessive stimulation of the reticular zone of the adrenal cortex by a non-ACTH-like factor or under the influence of b -endorphins, neurotransmitters, such as dopamine. When a critical body weight is reached (especially when its norm is exceeded), the peripheral conversion of androgens to estrogens increases, primarily in the liver and adipose tissue. An increase in the level of estrogen, primarily estrone, leads to hypersensitization of gonadotrophs in relation to luliberin (GnRH). At the same time, under the influence of estrone, the production of GnRH by the hypothalamus increases, the amplitude and frequency of impulses of its secretion increase, as a result of which the production of LH by the adenohypophysis increases, the LH / FSH ratio is disturbed, and relative FSH deficiency occurs. Strengthening the effect of LH on the ovaries contributes to an increase in the production of androgens by the thecal cells and their hyperplasia. A relatively low level of FSH leads to a decrease in the activity of FSH-dependent aromatase, and granulosa cells lose their ability to aromatize androgens into estrogens. Hyperandrogenism prevents the normal growth of follicles and contributes to the formation of their cystic atresia. Lack of growth and maturation of follicles further inhibits FSH secretion. The increased pool of androgens in peripheral tissues is converted into estrone. A vicious circle is closing.

Thus, the result of a violation of the central and peripheral mechanisms of regulation of steroidogenesis is the development of functional ovarian hyperandrogenism in patients with PCOS.

Pathogenesis of PCOS according to S.S.C. Yen is shown in Diagram 1:

Scheme 1.

In the early 80s, a number of authors proposed a new theory of the pathogenesis of polycystic ovary syndrome, different from the theory of S.S.C. Yen. It has been found that PCOS is associated with hyperinsulinemia, and this syndrome is characterized by both reproductive and metabolic disorders.

The relationship between hyperinsulinemia and hyperandrogenism was already pointed out in 1921 by Achard and Thieris. They described hyperandrogenism in an obese woman with type 2 diabetes and called this condition "bearded woman's diabetes."

Later, D. Bargen found that women with PCOS and hyperandrogenism had basal and glucose-stimulated hyperinsulinemia compared with the control group of women of the same weight, which suggested the presence of insulin resistance. A direct relationship between insulin and androgen levels was revealed, and it was suggested that hyperinsulinemia may be the cause of hyperandrogenism.

In 1988, G. Reaven first suggested that IR and compensatory hyperinsulinemia (GI) play a major role in the development of the syndrome of metabolic disorders. He called him "Syndrome X" . Currently, the term "metabolic syndrome" or "insulin resistance syndrome" is most often used.

Hypotheses of the pathogenesis of hyperinsulinemia and hyperandrogenism

The mechanism of occurrence of hyperandrogenism and hyperinsulinemia is not fully understood. Theoretically, three interactions are possible: hyperandrogenism (GA) causes GI; GI leads to GA: there is some third factor responsible for both phenomena.

1. The assumption that GA causes GI is based on the following facts. In women who take oral contraceptives containing progestins with "androgenic properties", impaired glucose tolerance is detected. Long-term administration of testosterone to transsexuals is accompanied by the occurrence of IR. It has been shown that androgens affect the composition of muscle tissue by increasing the number of muscle fibers of the second type, which are less sensitive to insulin compared to the fibers of the first type.

2. Most factors are in favor of GI leading to GA. It has been shown that IR persists in patients undergoing subtotal or total ovarian removal, as well as in women who have long-term use of GnRH agonists, when marked androgen suppression was noted. The administration of diazoxide, a drug that suppresses the release of insulin from the pancreas, caused a decrease in testosterone (T) levels and an increase in the level of sex steroid-binding globulin (SSBG) in patients with PCOS, obesity and hyperinsulinemia. Intravenous insulin administration to women with PCOS resulted in an increase in circulating levels of androstenedione and T. Measures aimed at increasing insulin sensitivity (weight loss, fasting, and a low-calorie diet) were accompanied by a decrease in androgen levels. There is evidence that insulin can directly suppress the production of SHBG by the liver, and in conditions of hyperinsulinemia this effect is enhanced. At the same time, it is believed that insulin, and not sex hormones, is the main regulator of SSSH synthesis. A decrease in the level of SSSG leads to an increase in the concentration of free and, therefore, biologically active T (normally 98% of T is in a bound state).

The hypothesis linking GA with hyperinsulinemia does not answer the question of how the ovary maintains insulin sensitivity in an insulin-resistant state of the body. Several possible explanations have been proposed. Since insulin has many functions, it can be assumed that some of them are selectively defective. Organ-specific insulin sensitivity may be observed. But more likely is the assumption that insulin acts on the ovary not only through insulin receptors, but also through receptors for insulin-like growth factors (IGF).

Insulin receptors and IGF-1 receptors have been identified in human ovaries (in ovarian stromal tissue of healthy women, women with PCOS, in follicular tissue and granulosa cells). Insulin can bind to IGF-1 receptors, although with less affinity than its own receptors. However, in HI, as well as in situations where insulin receptors are blocked or deficient, it can be expected that insulin will bind to IGF-1 receptors to a greater extent.

It is possible that the mechanisms of insulin/IGF-1 stimulation of steroidogenesis in the ovary can be divided into non-specific and specific. Nonspecific are the classical action of insulin on the metabolism of glucose, amino acids and DNA synthesis. As a result, the viability of the cell increases and, consequently, the synthesis of hormones increases. Specific mechanisms include direct action of insulin/IGF-1 on steroidogenic enzymes, synergism between insulin and LH/FSH, and effects on the number of LH receptors.

Insulin / IGF-1, acting synergistically with FSH, stimulates aromatase activity in granulosa cell culture and thereby increases the synthesis of estradiol. In addition, they lead to an increase in the concentration of LH receptors, enhancing LH-dependent synthesis of androstenedione by theca- and stromal cells.

The increasing concentration of androgens in the ovary under the action of insulin/IGF-1 causes atresia of the follicles, which leads to the gradual elimination of estrogen- and progesterone-producing granulosa cells, followed by hyperplasia of the thecal cells and luteinization of the interstitial tissue of the ovary, which are the site of androgen production. This explains the fact that the stimulation of ovarian steroidogenesis by insulin manifests itself mainly in the form of hyperandrogenism.

It has been suggested that insulin/IGF-1 can stimulate both LH-dependent cytochrome P450c17a activity in the ovaries and ACTH-dependent P450c17a activity in the adrenal glands. This, apparently, explains the frequent combination of ovarian and adrenal forms of hyperandrogenism in patients with PCOS.

A relationship with the S.S.C. theory is also possible. Yen on the involvement of adrenal steroidogenesis in the pathogenesis of PCOS (Figure 2).

Scheme 2. The action of insulin in polycystic ovary syndrome

V. Insler (1993), having studied the levels of insulin, IGF-1, growth hormone and their correlation with the levels of gonadotropins and androgens in women with PCOS, proposed two models for the development of this syndrome. In obese patients, GI causes an excess production of androgens through IGF-1 receptors, which, acting in synergy with LH, cause an increase in the activity of cytochrome P450c17a, the main controlling enzyme in androgen synthesis. In patients with normal body weight, a relative increase in the concentration of growth hormone stimulates excessive production of IGF-1. From this point on, synergism with LH leads to androgen hyperproduction by the same mechanism as in obese patients. An increase in the level of androgens causes a change in the function of the hypothalamic centers, leading to a violation of the secretion of gonadotropins and changes typical for PCOS (Scheme 3).

Scheme 3. Pathogenesis of polycystic ovary syndrome

The molecular mechanisms leading to the development of insulin resistance are not fully understood. However, recent advances in molecular biology have made it possible to determine the structure of the gene encoding the insulin receptor in women with ovarian hyperandrogenism.

Moller and Flier studied the sequence of amino acids in the structure of DNA chains in patients with ovarian hyperandrogenism. They found a substitution of tryptophan for serosine at codon 1200. The researchers suggested that this change disrupts the activation of the tyrosine kinase system in the insulin receptor. Low activity of insulin receptors leads to the development of IR and compensatory GI.

Yoshimasa et al. described another point mutation variant in a patient with hyperandrogenism, insulin resistance, and acanthosis nigricans. They found a substitution of serine for arginine in the tetrameric structure of the insulin receptor. This mutation in the active locus resulted in the impossibility of connecting the a- and b-subunits, as a result of which the functionally active receptor was not synthesized. These studies are only the first attempts to identify a specific genetic etiology of ovarian stromal tecomatosis.

Later, Dunaif A. notes that in polycystic ovary syndrome, IR may be due to a violation of autophosphorylation of the insulin receptor b-subunits (iR), the cytoplasmic part of which has tyrosine kinase activity. At the same time, insulin-independent phosphorylation of serine residues (CPOS-ser) increases with suppression of tyrosine kinase activity (a secondary signal transmitter that determines insulin sensitivity to the receptors of the same name). This defect is typical only for PCOS-dependent IR; in other insulin-resistant states (obesity, NIDDM), these changes are not detected.

It cannot be ruled out that some serine phosphorylating factor exists in PCOS-ser. For example, a serine/threonine phosphatase inhibitor is isolated, which, apparently, disrupts uR phosphorylation in PCOS-ser. This compound is similar to the recently isolated membrane glycoprotein PC-1 (inhibitor of insulin receptor tyrosine kinase), but the latter does not increase insulin-independent phosphorylation of serine and R.

Tumor necrosis factor-a (TNF-a) has similar properties: phosphorylation of serine residues IRS-1 (one of the secondary transmitters of the uR signal) under the influence of TNF-a leads to suppression of tyrosine kinase activity of uR.

Moller et al. found that phosphorylation of human P450c17 serine, a key enzyme regulating the biosynthesis of adrenal and ovarian androgens, increased 17,20-lyase activity. Modulation of the enzymatic activity of steroidogenesis by serine phosphorylation has been described for 17b-hydroxysteroid dehydrogenase. If we assume that the same factor (enzyme) phosphorylates insulin receptor serine, causing IR, and P450c17 serine, causing hyperandrogenism, then the relationship between PCOS and IR can be explained. In vitro experiments have shown that protein kinase A (serine/threonine kinase) catalyses serine phosphorylation of insulin receptors (Scheme 4).

Scheme 4. Insulin resistance gene in PCOS

Thus, according to the results of a study conducted by Brzechffa et al. (1996), a significant proportion of women in the PCOS population have leptin levels higher than expected based on their BMI, free testosterone, and insulin sensitivity. On the other hand, recent work in this area has not shown significant differences in leptin levels in the study groups with PCOS and in the control groups. In addition, it was found that the content of leptin is not affected by the basal level of insulin, the content of gonadotropins and sex steroids. However, Zachow and Magffin (1997), taking into account the presence of leptin receptor mRNA in ovarian tissue, demonstrated a direct effect of this hormone on rat granulosa cell steroidogenesis in vitro. At the same time, a dose-dependent inhibitory effect of leptin on IGF-1 was shown, potentiated by an increase in FSH-stimulated E 2 synthesis by granulosa cells. These data support the hypothesis that increased leptin levels in obese individuals may counteract dominant follicle maturation and ovulation. Very interesting are the data of Spicer and Franciso (1997), indicating that leptin in increasing concentrations (10-300 ng/ml) inhibits insulin-dependent production of E 2 and progesterone in granulosa cell culture. This effect is due to the presence of specific binding sites for leptin. By analogy with this, it can be assumed that a high level of leptin can reduce the sensitivity of other target tissues to the action of endogenous insulin, leading to the development of IR in obesity.

Diagnosis

Diagnosis of the syndrome of ovarian hyperandrogenism in a typical clinical picture is not difficult. First of all, this is a violation of menstrual function by the type of oligo-, opso- or amenorrhea, anovulation and the primary or secondary infertility caused by it, hirsutism, acne, 40% of patients have obesity of varying severity. A gynecological examination reveals a bilateral increase in the size of the ovaries, often against the background of a hypoplastic uterus.

An important place in the diagnosis of PCOS is occupied by hormonal research methods. aimed at identifying hyperandrogenism, its source and determining the level of gonadotropic hormones: LH and FSH. In patients with PCOS, there is often a predominance of the level of LH over FSH, their ratio is disturbed and increased (more than 2.5-3). The level of prolactin is normal, although some increase is observed in 30% of patients.

The level of urinary excretion of total 17-CS in PCOS varies widely and is not very informative. Determination of 17-KS fractions (DGA, 11-oxidized ketosteroids, androsterone, etiocholanolone) also does not provide identification of the localization of the source of hyperandrogenism. Confirmation of the ovarian source of hyperandrogenism is an increase in the level of androstenedione (A) and testosterone (T) in the blood and an increase in the A / T ratio. The adrenal genesis of hyperandrogenism is confirmed by an increase in the level of dehydroepiandrosterone (DHA) and its sulfate (DHA-C) and 17-hydroxyprogesterone (17-OH-P) in the blood. To clarify the localization of the source of hyperandrogenism, various functional tests have been proposed, the most common of which is the test with dexamethasone, synacthen depot.

Taking into account the discovery of new pathogenetic links in the development of PCOS, to assess the state of carbohydrate metabolism, it is necessary to carry out a standard glucose tolerance test (75 ml of glucose per os) with the determination of glucose levels and immunoreactive insulin (IRI). Evidence in favor of insulin resistance is also a BMI over 25 and OT / OB over 0.85, as well as dyslipidemia.

Treatment

The modern approach to the pathogenetic treatment of PCOS is based on the principle of restoring impaired ovarian function , that is, the elimination of anovulation, which in turn leads to a decrease in hyperandrogenism and the restoration of folliculogenesis. However, the study of the features of the etiopathogenesis of ovarian hyperandrogenism leads to the conclusion that the choice of methods for adequate treatment of PCOS is not an easy task.

Combined oral contraceptives - the most commonly used group of drugs for PCOS. The mechanism of action is to suppress elevated LH, normalize the LH / FSH ratio, increase the synthesis of SSSH by the liver. After cancellation, a “rebound effect” is achieved, which consists in the normalization of the hypothalamic-pituitary function, the reduction of androgen hyperproduction by ovarian tissue, the normalization of folliculogenesis and the restoration of ovulation.

Treatment is carried out according to the standard scheme: 1 tablet per day from the 5th to the 25th day of the cycle for 3-6 months. If necessary, the courses are repeated. However, it is known that long-term use of estrogen-progestin contraceptives can lead to hyperinsulinemia, thereby aggravating the main pathogenetic link of PCOS.

Some contraceptives contain progestogen components derived from 19-norsteroids (norethisterone, levonorgestrel), which have varying degrees of androgenic effects, and therefore the prescription of drugs containing these components in patients with hirsutism is limited. It is more advisable for symptoms of hyperandrogenism to use oral contraceptives with a progestogen without androgenic action.

It is possible to use progestin preparations devoid of androgenic properties in the form of monotherapy, especially with endometrial hyperplasia. Dydrogesterone is prescribed 1 tablet (10 mg) 2 times a day from 14-16 to 25 days of the cycle lasting from 3 to 6 courses.

The most effective means of stimulating ovulation in PCOS is an antiestrogen drug. clomiphene citrate . The main effects of antiestrogens are a decrease in pituitary hypersensitivity to the action of GnRH, a decrease in LH production, induction of an ovulatory LH surge, and stimulation of ovulation. The drug is prescribed at 50 mg, 100 mg per day from 5 to 9 days of the cycle until ovulation is achieved according to functional diagnostic tests, but not more than 3 courses in a row. Recently, there have been publications on the effect of clomiphene citrate on the insulin-insulin-like growth factor system. They indicated that by the 5th day of the stimulation of ovulation with clomiphene (150 mg/day), a progressive decrease (by a maximum of 30%) in the level of IGF-1 was determined. However, in a number of other similar studies, a significant decrease in basal insulin levels in response to the administration of clomiphene was not found.

The advent of drugs with antiandrogenic properties has greatly expanded the therapeutic options for PCOS. The most widely used drug is Diane-35, containing 35 mg of ethinyl estradiol and 2 mg of cyproterone acetate. In addition to the action characteristic of oral contraceptives, the drug blocks the action of androgens at the level of target cells, in particular, hair follicles. The latter leads to a decrease in hirsutism. The drug is used according to the standard scheme, as an oral contraceptive in courses of 6 or more cycles. However, it should be noted that these drugs have a negative effect on lipid and carbohydrate metabolism, which manifests itself in an increase in the level of cholesterol, low density lipoproteins, as well as an increase in hyperinsulinemia, which requires constant dynamic monitoring of these indicators in patients with PCOS. Spironolactone, which is widely used in the treatment of androgen-dependent dermopathies, also has antiandrogenic properties.

One of the main directions in the modern therapy of ovarian hyperandrogenism is the search and use of drugs and agents aimed at eliminating insulin resistance and compensatory hyperinsulinemia.

First of all, these are measures that ensure the reduction of excess body weight: a low-calorie diet (within 1500-2200 kcal / day) with restriction of fats and easily digestible carbohydrates, restriction of salt intake to 3-5 g per day, moderate physical activity, normalization of the work regime and rest. It is possible to use drugs that help reduce BMI, for example, orlistat, which selectively inhibits gastrointestinal lipases (“fat blocker”) or sibutramine, which blocks the reuptake of noradrenaline and serotonin in the synapses of the hypothalamic “satiation” center. Increased energy expenditure (thermogenesis) is also due to a synergistic interaction between enhanced norepinephrine and serotonin function in the central nervous system. This is expressed in the selective activation of the central sympathetic effect on brown adipose tissue due to indirect activation of b 3 -adrenergic receptors.

The next step is the use of drugs that improve the impaired sensitivity of tissues to the action of insulin. There are data in the literature on the reduction of hyperandrogenism and the restoration of menstrual and ovulatory function when prescribing drugs of a number of biguanides (metformin /Siofor®/, Berlin-Chemie). They potentiate the action of insulin at the receptor and post-receptor levels and significantly improve the sensitivity of tissues to this hormone. Some studies have shown a significant decrease in fasting insulin levels and 2 hours after a 75 g glucose load in women with PCOS treated with metformin. This decrease correlated with a decrease in androgen levels. It should also be noted that the use of biguanides, which normalize carbohydrate disorders, often leads to a decrease in BMI in obese patients and has a positive effect on lipid metabolism.

The world literature reports the results of the use of drugs belonging to the class of thiazolidinediones. Studies have shown that during treatment troglitazone (200-400 mg / day) improves insulin sensitivity in women with PCOS, androgen levels decrease. However, the revealed cytotoxic, hepatotoxic effect of this group of drugs limits the possibility of their widespread use. A search is underway for new drugs that selectively affect insulin sensitivity.

Despite a significant arsenal of various agents used to treat ovarian hyperandrogenism, the therapy of this pathology should be comprehensive and consistent, taking into account the leading pathogenetic link at this stage of treatment.

Treatment of women with PCOS should be aimed not only at correcting the identified symptoms of this disease, but also at preventing possible future complications. It is very important to suppress the excess secretion of androgens and induce the stability of monthly menstrual bleeding, which is successfully achieved with the use of drugs with antiandrogenic properties (Diana-35).

In case of ineffectiveness of conservative therapy after a year, the question of surgical treatment can be raised - laparoscopy with wedge resection of the ovaries or their laser vaporization . The effectiveness of surgical treatment is high (up to 90-95% of ovulation recovery), and preliminary pathogenetic therapy increases the stability of the achieved result.

Ethinylestradiol + cyproterone acetate

Diane-35 (trade name)

(Shering AG)

Hyperandrogenism is a phenomenon in which a woman's body produces an excessive amount of male androgen hormones. Their excess causes serious deviations in the work of internal organs and systems. The greatest danger is for women who plan to conceive and bear a child. Ovarian hyperandrogenism causes infrequent and scanty menstruation, can cause infertility and lack of ovulation.

Hyperandrogenism is a dangerous condition in which a woman cannot conceive and bear a fetus. Due to the excess amount of male hormones in the ovaries, normal maturation of the follicles does not occur. At the same time, the female genital organ is overgrown with connective tissue, which is why the egg cannot normally exit the follicles. Due to pathology, women develop serious pathologies, including polycystic ovaries: the level of insulin, anti-Müllerian hormone, testosterone, androstenedione rises in the blood. The following diseases can provoke such a disease:

• An excessive amount of LH in the blood, which arose against the background of pathologies of the hypothalamus and adenohypophysis.
• Excess production of male sex steroid hormones during the prepubertal period.
• Excess body weight, joined in the prepubertal period.
• Insulin resistance or deficiency in the body.
• Violation of the production of steroids in the female ovaries.
• Primary hormone deficiency.

Studies have shown that hyperandrogenism of ovarian origin in most cases occurs against the background of congenital pathology of the adrenal glands.

Symptoms

In the initial stages, diagnosing hyperandrogenism of ovarian genesis is quite difficult. This pathology does not cause any symptoms for a long time. Over time, the following symptoms appear:

• Excessive hair growth of the skin: hair appears on the abdomen, chest, cheeks.
• Alopecia on the head.
• Numerous rashes on the skin: acne, pimples, peeling.
• The development of osteoporosis - thinning of bone tissue.
• development of muscle atrophy.

You can also diagnose signs of ovarian hyperandrogenism by clinical manifestations:

• The development of type 2 diabetes - an increase in blood glucose levels.
• A sharp set of excess body weight.
• An increase in blood pressure.
• Inability to conceive a child or frequent miscarriage.
• The formation of the genital organs according to the intermediate type.

Quite often, women with hyperandrogenism experience depression and excessive fatigue. This condition can also occur in younger patients.

Diagnostics

It is quite difficult to determine ovarian hyperandrogenism - for a long time this disease does not manifest itself with any distinctive symptoms. In this case, the first signs may occur in a girl at the very beginning of puberty or upon reaching reproductive age. The earlier the pathology is diagnosed, the easier it is to get rid of it. To determine the disease, it is necessary to carry out the following studies:

• Measure your hormone levels before, during and after your period.
• Determine the level of sex hormones in the urine.
• Perform an ultrasound of the pelvic organs.
• Examine the kidneys and adrenal glands.
• Get an MRI of the internal organs.
• If necessary, laparoscopy is performed - a study that allows you to determine the nature of the cells.

The pathological manifestation in a person of pronounced characteristic features inherent in the opposite sex often provokes adrenal hyperandrogenism (adrenogenital syndrome). With the development of this syndrome in the body, an increased content of androgens (steroid male sex hormones) is observed, leading to virilization.

General information

Virilization (masculinization) of adrenal genesis is caused by excessive production of androgen-type hormones by the adrenal glands and leads to external and internal changes that are atypical for the patient's gender. Androgens are necessary in the body of an adult woman, as they are responsible for important transformations of the body during puberty. In particular, they produce the synthesis of estrogen, and also contribute to the strengthening of bone tissue, muscle growth, are involved in the regulation of the liver and kidneys, and the formation of the reproductive system. Androgens are produced mainly by the adrenal glands and in the female body by the ovaries, and in the male, respectively, by the testicles. A significant excess of the content of these hormones in women can significantly upset the reproductive system and even provoke infertility.

Causes of adrenal hyperandrogenism

The main reason for the accumulation of androgens in the body is a congenital defect in the synthesis of enzymes that prevents the conversion of steroids. Most often, the deficiency of C21-hydroxylase, which synthesizes glucocorticoids, acts as such a defect. In addition, hormonal imbalance is a consequence of the influence of hyperplasia of the adrenal cortex or tumor-like formations (some types of adrenal tumors are able to produce hormones). Congenital adrenal hyperandrogenism is most often diagnosed. However, sometimes there are also cases of the development of hyperandrogenism due to tumors of the adrenal glands that secrete androgens (Itsenko-Cushing's disease).

Pathogenesis

C21-hydroxylase deficiency can be successfully compensated by the adrenal glands for some time and passes into a decompensated phase during stressful hormonal fluctuations that are created by emotional upheavals and changes in the reproductive system (the onset of sexual relations, pregnancy). When the defect in the synthesis of enzymes becomes pronounced, the conversion of androgens into glucocorticoids stops and there is an excessive accumulation of them in the body.

Features of the development of adrenogenital syndrome in women

Adrenogenital syndrome in women leads to serious changes in the functioning of the ovaries and disorders in the reproductive system. According to statistical studies, every fifth woman suffers from hyperandrogenism to some extent with various manifestations. Moreover, age in this case does not matter, the disease manifests itself at any stage of the life cycle, starting from infancy.

The impact of hyperandrogenism on ovarian function causes the following manifestations:

• inhibition of growth and development of follicles in the early phase of folliculogenesis is manifested by amenorrhea (absence of menstruation for several cycles);
• slowing down the growth and development of the follicle and the egg, which is not capable of ovulation, can manifest itself as anovulation (lack of ovulation) and oligomenorrhea (an increase in the interval between menstruation);
• ovulation with a defective corpus luteum, is expressed in the insufficiency of the luteal phase of the cycle, even with regular menstruation.

Symptoms of adrenal hyperandrogenism

Adrenogenital syndrome has primary and secondary manifestations, depending on the phase of the development of the disease and the factors of its occurrence. Indirect signs of the presence of adrenal hyperandrogenism in a woman are frequent colds, a tendency to depression, and increased fatigue.

The main symptoms of adrenal hyperandrogenism:

• increased hair growth (limbs, abdomen, mammary glands), up to hirsutism (hair growth on the cheeks);
• baldness with the formation of bald patches (alopecia);
• skin defects (acne, acne, peeling and other inflammations);
• muscle atrophy, osteoporosis.

The secondary symptoms of adrenogenital syndrome are the following manifestations:

• arterial hypertension, manifested in the form of seizures;
• elevated blood glucose levels (type 2 diabetes);
• rapid weight gain, up to obesity, in need of therapy;
• intermediate type of formation of female genital organs;
• lack of menstruation or significant intervals between menstruation;
• infertility or miscarriage (for a successful pregnancy, a certain amount of female hormones in the body is necessary, the production of which practically stops in the event of hyperandrogenism).