Polycystic ovary syndrome

Polycystic ovary syndrome is a multifactorial heterogeneous pathology characterized by irregularities in the menstrual cycle, chronic anovulation, hyperandrogenia, cystic ovarian changes and infertility. Polycystic ovary syndrome is characterized by moderate obesity, irregular monthly or amenorrhea and symptoms of an excess of androgens (hirsutism, acne). Usually the ovaries contain many cysts. Diagnosis is based on pregnancy tests, hormone levels and examination to exclude virilizing tumors. Treatment is symptomatic.

[1], [2], [3], [4], [5], [6],

Epidemiology

The frequency of polycystic ovary syndrome among women of reproductive age is 8-15%, among causes of infertility 20-22%, among women with endocrine infertility - 50-60%.

[7], [8], [9], [10], [11], [12]

Causes of the polycystic Ovary Syndrome

Polycystic ovary syndrome is a common endocrine pathology of the reproductive system, occurring in 5-10% of patients; characterized by the presence of anovulation and an excess of androgens of an unclear etiology. Ovaries can be of normal size or enlarged, with a smooth, thickened capsule. As a rule, the ovaries contain many small, 26 mm-thick follicular brushes; sometimes there are large cysts containing atretic cells. An increase in estrogen levels is noted, which leads to an increased risk of endometrial hyperplasia and, ultimately, endometrial cancer. Often there is an increase in androgen levels, which increases the risk of metabolic syndrome and hirsutism.

[13]

Pathogenesis

Women with polycystic ovary syndrome (PCOS) have abnormalities in the metabolism of androgens and estrogens, the broken synthesis of androgens. The disease is accompanied by high concentrations in the serum of androgen hormones, such as testosterone, androstenedione, dehydroepiandrosterone sulfate and (DHEA-S). However, normal levels of androgens can sometimes be determined.

PCOS is also associated with insulin resistance, hyperinsulinemia and obesity. Hyperinsulinemia can also lead to suppression of the synthesis of SHBG, which, in turn, can enhance the signs of androgenism.

In addition, insulin resistance in polycystic ovary syndrome is associated with adiponectin, a hormone secreted by adipocytes, which regulates lipid metabolism and blood glucose levels.

Elevated levels of androgens are accompanied by an increase in the stimulating effect of luteinizing hormone (LH), secreted by the anterior pituitary gland, which leads to an increase in the flow of ovarian cells. These cells, in turn, increase the synthesis of androgens (testosterone, androstenedione). Because of the lowered level of follicle-stimulating hormone (FSH) in relation to LH, granular ovarian cells can not aromatize androgens in estrogens, which leads to a decrease in the level of estrogens and subsequent anovulation. 

Some evidence suggests that patients have a functional disorder of cytochrome P450c17, 17-hydroxylase, which inhibit the biosynthesis of androgens.

Polycystic ovary syndrome is a genetically heterogeneous syndrome. Studies of family members with PCOS prove autosomal dominant inheritance. A genetic link between PCOS and obesity was recently confirmed. The variant of the FTO gene (rs9939609, which predisposes to general obesity) is significantly associated with the susceptibility to the development of PCOS. Polymorphisms of the 2p16 locus (2p16.3, 2p21 and 9q33.3), which are associated with polycystic ovary syndrome, and the gene that encodes receptor of luteinizing hormone (LH) and chorionic gonadotropin (HG).

[14], [15], [16], [17], [18]

Symptoms of the polycystic Ovary Syndrome

Symptoms of the syndrome of polycystic ovaries appear during puberty, manifestation of them decreases with time. The presence of regular menstruation for some time after menarche excludes the diagnosis of polycystic ovary syndrome. During the examination, usually there is abundant cervical mucus (this reflects high estrogen levels). The diagnosis of polycystic ovary syndrome can be suspected if a woman has at least two typical symptoms (moderate obesity, hirsutism, irregular menstrual or amenorrhea).

The most common combination of the following clinical symptoms:

• violation of the menstrual cycle (oligomenorrhea, dysfunctional uterine bleeding, secondary amenorrhea);
• anovulation;
• infertility;
• hirsutism;
• violation of fat metabolism (obesity and metabolic syndrome);
• diabetes;
• obstructive sleep apnea syndrome.

Forms

Conventionally, the following forms of the syndrome of polycystic ovaries can be distinguished:

• central genesis;
• adrenal origin;
• ovarian genesis.

[19], [20], [21], [22]

Diagnostics of the polycystic Ovary Syndrome

Diagnosis is based on the exclusion of pregnancy (pregnancy test), as well as the study of estradiol, FSH, TSH and prolactin in the serum. The diagnosis is confirmed by ultrasonography, which reveals more than 10 follicles in the ovary; Follicles usually occur on the periphery and resemble a string of pearls. If there is a presence of follicles in the ovaries and hirsutism, then it is necessary to determine the levels of testosterone and DHEAS. Pathological levels are evaluated as in amenorrhea.

[23], [24], [25], [26], [27], [28]

Anamnesis and physical examination

Carrying out a careful collection of anamnesis, hereditary factors of the development of the syndrome of polycystic ovaries are revealed. On examination, the body mass index and the ratio of the waist circumference to the hip circumference (in the norm ≤ 0,8) are calculated for the diagnosis of excess body weight and obesity.

Polycystic ovary syndrome is characterized by polymorphism of clinical and laboratory signs.

[29], [30]

Special methods for diagnosis of polycystic ovary syndrome

Be sure to carry out hormonal examination on the 3-5th day of menstrual reactions: in the blood determine the level of LH, FSH, prolactin, testosterone, adrenal androgens - DHEAS, 17-hydroxyprogesterone. Polycystic ovary syndrome is characterized by a high index of LH / FSH -> 2.5-3 (due to increased levels of LH) and hyperandrogenism.

In order to clarify the source of hyperandrogenia, a test with ACTH for a differential diagnosis with hyperandrogenism is carried out, caused by a mutation of the gene encoding the enzyme 21-hydroxylase in the adrenal glands (diagnosis of erased and latent forms of adrenogenital syndrome). Technique: at 9 o'clock in the morning, blood is withdrawn from the ulnar vein, then intramuscularly injected 1 mg of the synakten-depot preparation, after 9 hours - repeated blood sampling. In both blood portions, the concentration of cortisol and 17-hydroxyprogesterone is determined, then a coefficient is calculated using a special formula, the values of which should not exceed 0.069. In these cases, the sample is negative and the woman (or man) is not a carrier of the 21-hydroxylase gene mutation.

A sample with diphenin is used to detect central forms of polycystic ovary and the possibility of treatment with drugs of neurotransmitter. Sample technique: the initial concentration of LH and testosterone is determined in the blood, then diphenin is taken 1 tablet 3 times a day for 3 days, after which the concentration of these same hormones is repeatedly determined in the blood. The sample is considered positive if the level of LH and testosterone decreases.

• With ultrasound of the genital organs, enlarged ovaries (10 cm ³ or more), a number of follicles up to 9 mm in diameter, ovarian stroma consolidation, and capsule thickening are determined.

• In addition, if suspected of insulin resistance, a glucose tolerance test is performed to determine the level of insulin and glucose before and after the load.
• If a suspected adrenal genesis of the polycystic ovary syndrome is recommended, genetic counseling and HLA genotyping are recommended.
• Hysterosalpingography.
• Laparoscopy.
• Assessment of fertility of the sperm of the spouse.

In November 2015, the American Association of Clinical Endocrinology (AACE), the American College of Endocrinology (ACE) and the Society for the Study of Androgen Reduction and PCOS (AES) released new recommendations in the diagnosis of PCOS. These recommendations are:

1. Diagnostic criteria of PCOS should include one of the following three criteria: chronic anovulation, clinical hyperandrogenism and polycystic ovary polycystic.
2. In addition to clinical findings, the level of 17-hydroxyprogesterone and antimuler hormone in serum should be determined for the diagnosis of PCOS.
3. Analysis of the free testosterone level is more sensitive to determining an excess of androgens than the level of total testosterone.

Differential diagnosis

Differential diagnostics is performed with other diseases, in which menstrual cycle disorders, hyperandrogenism and infertility are also observed: adrenogenital syndrome, adrenal and ovarian tumors, and Itenko-Cushing syndrome.

[31], [32], [33]

Treatment of the polycystic Ovary Syndrome

Women who have anovulatory menstrual cycles (no history or irregular menstruation and no evidence of progesterone production), in the absence of hirsutism and unwillingness to conceive, are prescribed intermittent progestin (for example, medroxyprogesterone 5-10 mg orally once a day for 10- 14 days of each month for 12 months) or oral contraceptives to reduce the risk of hyperplasia and endometrial cancer and reduce the level of circulating androgens.

Women who have polycystic ovary syndrome with anovulatory cycles, with hirsutism and who do not plan pregnancy, the treatment is aimed at reducing hirsutism and regulating the levels of testosterone and DHEAS in the serum. Women who want to become pregnant are treated for infertility.

Treatment of infertility in the syndrome of polycystic ovaries is carried out in 2 stages:

• 1 st stage - preparatory;
• The second stage is the stimulation of ovulation.

Therapy at the preparatory stage depends on the clinical and pathogenetic form of the polycystic ovary syndrome.

• In the syndrome of polycystic ovaries and obesity, the appointment of drugs that contribute to reducing insulin resistance is indicated: the drug of choice, metformin, is administered orally 500 mg 3 times daily for 3-6 months.
• In the ovarian form of the polycystic ovary syndrome and high levels of LH, drugs that reduce the sensitivity of the hypothalamic-pituitary system to complete suppression of ovarian function (estradiol level in the serum <70 pmol / L) are used:
  • Buserelin spray, 150 mcg in each nostril 3 times a day from the 21st or 2nd day of the menstrual cycle, the course is 1-3 months, or
  • Buserelin depot in / m 3.75 mg once every 28 days from the 21st or 2nd day of the menstrual cycle, the course is 1-3 months, or
  • leuprorelin n / c 3.75 mg once every 28 days from the 21st or 2nd day of the menstrual cycle, the course is 1-3 months, or
  • tryptorelin n / k 3.75 mg once in 28 days or 0.1 mg once a day from the 21st or 2nd day of the menstrual cycle, the course 1-3 months.

It is of no fundamental importance on which (the 21st or the 2nd) day of the menstrual cycle to appoint GnRH agonists, however, the appointment from the 21st day is preferable, since in this case no ovarian cysts are formed. When administered from the 2nd day of the cycle, the activation phase preceding the suppression phase in the mechanism of action of the GnRH agonist coincides with the follicular phase of the cycle and can cause the formation of ovarian cysts.

Alternative preparations:

• ethinyl estradiol / dienogest intraperitoneally 30 μg / 2 mg once a day from the 5th to the 25th day of the menstrual cycle, course 3-6 months or
• ethinyl estradiol / cyproterone acetate inside 35 μg / 2 mg once a day from the 5th to the 25th day of the menstrual cycle, the course 3-6 months.
• With the adrenal form of the syndrome of polycystic ovaries, the appointment of glucocorticoid drugs is indicated:
  • Dexamethasone inside 0.25-1 mg once a day, course 3-6 months, or
  • methylprednisolone inside 2-8 mg once a day, course 3-6 months, or
  • prednisolone 2.5-10 mg once a day, the course of 3-6 months.
• With the central form of the syndrome of polycystic ovaries anticonvulsants are used:
  • diphenin 1 tablet 1-2 times a day;
  • carbamazepine oral by 100 mg 2 times a day, the course 3-6 months.

At the second stage, ovulation is stimulated.

The choice of preparations and the regimens for their administration are determined taking into account clinical and laboratory data. During the induction of ovulation, a thorough ultrasound and hormonal monitoring of the stimulated cycle is performed.

It is unacceptable to conduct induction of ovulation with any medication without ultrasound monitoring. It is inappropriate to start the induction of ovulation with cystic formations in the ovaries> 15 mm in diameter and the thickness of the endometrium> 5 mm.

Induction of ovulation with clomiphene is indicated for a long history of the disease in young women with a sufficient level of estrogens (serum estradiol <150 pmol / L) and a low level of LH (> 15 IU / L).

Clomiphene is administered orally 100 mg once a day from the 5th to the 9th day of the menstrual cycle at the same time of day.

The control ultrasound is performed on the 10th day of the cycle, the diameter of the dominant follicle and the thickness of the endometrium are evaluated. Examinations are carried out every other day, in the period of the period, daily. It does not matter the day of the cycle, but the size of the leading follicle: if its diameter is more than 16 mm, then it is necessary to carry out an ultrasound scan daily until reaching a size of 20 mm.

Alternative treatment regimens (with pronounced antiestrogenic effect):

Scheme 1:

• clomiphene inside 100 mg once a day from the 5th to the 9th day of the menstrual cycle at the same time of day +
• ethinyl estradiol (EE) orally 50 μg twice a day from the 10th to the 15th day of the menstrual cycle or
• Estradiol inside 2 mg twice a day from the 10th to the 15th day of the menstrual cycle.

Scheme 2:

• clomiphene inside 100 mg once a day from the 3rd to the 7th day of the menstrual cycle at the same time of day +
• menotropins in / m 75-150 IU once a day at the same time from the 7th to 8th day of the menstrual cycle or
• follitropin alfa IM 75-150 IU once a day at the same time from the 7th to 8th day of the menstrual cycle.

Induction of clomiphene ovulation by citrate is not indicated in the following situations:

• when hypoestrogenia (serum estradiol level <150 pmol / l);
• after preliminary preparation by GnRH agonists (hypoestrogenia develops as a result of hypothalamic-pituitary-ovarian system sensitivity decrease);
• in women of senior reproductive age, with a long history of the disease and a high level of LH in the blood serum (> 15 IU / L). It is not advisable to increase the dose of clomiphene to 150 mg / day with repeated courses of stimulation, as the negative peripheral antiestrogenic effect intensifies.

Do not recommend more than 3 courses of stimulation with clomiphene; If treatment is ineffective, gonadotropins should be used.

Stimulation of ovulation by gonadotropins is indicated in the absence of adequate folliculogenesis after stimulation with clomiphene, in the presence of pronounced peripheral anti-estrogenic effect, insufficient estrogen saturation. It can be performed both in young patients and in late reproductive age.

Drugs of choice:

• menotropins in / m 150-225 IU once a day from the 3-5th day of the menstrual cycle at the same time, the course is 7-15 days or
• urofollitropin in / m 150-225 IU once a day from the 3-5th day of the menstrual cycle at the same time, the course is 7-15 days.

Alternative drugs (with a high risk of ovarian hyperstimulation syndrome):

• follitropin alfa v / m 100-150 IU once a day from the 3-5th day of the menstrual cycle at the same time, the course is 7-15 days. The induction of ovulation by gonadotropins with the use of GnRH analogs is indicated in the presence of a syndrome of polycystic ovaries with a high level of LH in blood serum (> 15 IU / l).

Drugs of choice:

• Buserelin in the form of a spray of 150 mcg in each nostril 3 times a day from the 21st day of the menstrual cycle or
• buserelin depot in / m 3.75 mg once on the 21st day of the menstrual cycle;
• leuprorelin n / k 3.75 mg once on the 21st day of the menstrual cycle;
• tryptorelin n / k 3.75 mg once on the 21st day of the menstrual cycle or 0.1 mg once a day from the 21st day of the menstrual cycle +
• Menotropinum m / m 225-300 IU once a day from the 2-3rd day of the next menstrual cycle at the same time.

Alternative drugs (with a high risk of ovarian hyperstimulation syndrome):

• menotropins in / m 150-225 IU once a day from the 2nd to 3rd day of the menstrual cycle at the same time or
• follitropin alfa v / m 150-225 IU once a day from the 2nd to 3rd day of the menstrual cycle at the same time +
• ganirelix n / k 0.25 mg once a day, starting from the 5th-7th day of gonadotropins (when reaching the dominant follicle size of 13-14 mm);
• cetrorelix n / k 0.25 mg once a day, starting with the 5-7th day of gonadotropin use (when reaching the dominant follicle size of 13-14 mm).

Induction of ovulation in patients of late reproductive age (with a weak ovarian response to gonadotropic drugs).

Drugs of choice:

• menotropins in / m 225 IU once a day from the 3-5th day of the menstrual cycle at the same time +
• tryptorelin n / k 0.1 mg once a day from the 2nd day of the menstrual cycle.

Alternative preparations:

• tryptorelin n / k 0.1 mg once a day from the 2nd day of the menstrual cycle +
• follitropin alfa v / m 200-225 IU once a day from the 3-5th day of the menstrual cycle at the same time.

In all schemes with the use of gonadotropins, the adequacy of the dose of the latter is estimated by the dynamics of follicular growth (at a rate of 2 mm / day). With slow growth of the follicles, the dose is increased by 75 IU, with too rapid growth decreases by 75 IU.

In all schemes, in the presence of a mature follicle 18-20 mm in size, the thickness of the endometrium is not less than 8 mm, therapy is discontinued and gonadotropin chorionic IM is given 10,000 units once.

After the ovulation is established, the luteal phase of the cycle is supported.

Drugs of choice:

• dydrogesterone orally 10 mg 1-3 times a day, course 10-12 days or
• progesterone inside by 100 mg 2-3 times a day, or in the vagina 100 mg 2-3 times a day, or in / m 250 mg once a day, the course 10-12 days. Alternative drug (in the absence of symptoms of ovarian hyperstimulation):
• gonadotropin chorionic in / m 1500-2500 units 1 time per day for 3.5 and 7 days of the luteal phase.

Other drugs used in the treatment of PCOS:

• Antiandrogens (for example, spironolactone, leuprolide, finasteride).
• Sugar-reducing drugs (for example, metformin, insulin).
• Selective modulators of estrogen receptors (eg, clomiphene citrate).
• Drugs for the treatment of acne (for example, benzoyl peroxide, tretinoin cream (0.02-0.1%) / gel (0.01-0.1%) / solution (0.05%), adapalene cream (0.1% ) / gel (0.1%, 0.3%) / solution (0.1%), erythromycin 2%, clindamycin 1%, sodium Sulfamethamide 10%).

Side effects of treatment

When clomiphene is used, the majority of patients develop a peripheral anti-estrogenic effect, which consists in lagging the growth of the endometrium from the growth of the follicle and reducing the amount of cervical mucus. With the use of gonadotropins, especially human menopausal gonadotropin (menotropins), the development of the ovarian hyperstimulation syndrome (OCS) is possible, with the use of recombinant FSH (follitropin alfa), the risk of ovarian hyperstimulation syndrome is less. When using schemes involving GnRH agonists (tryptorelin, buserelin, leuprorelin), the risk of ovarian hyperstimulation syndrome increases, and the use of GnRH agonists can cause symptoms of estrogen deficiency - hot flashes, dry skin and mucous membranes.

Forecast

The effectiveness of infertility treatment in the syndrome of polycystic ovaries depends on the clinical and hormonal features of the course of the disease, the age of the woman, the adequacy of the preparatory therapy, the correctness of the selection of the scheme for induction of ovulation.

In 30% of young women with a short history of the disease, it is possible to achieve pregnancy after pre-treatment without induction of ovulation.

The effectiveness of stimulation of ovulation with clomiphene does not exceed 30% per woman, 40% of patients with polycystic ovary syndrome are clomiphene-resistant.

The use of menotropins and urofollitropine allows pregnancy to be achieved in 45-50% of women, but these drugs increase the risk of ovarian hyperstimulation syndrome.

The most effective schemes are the use of GnRH agonists, which allow to avoid "parasitic" LH peaks: up to 60% of pregnancies per 1 woman. However, when using these drugs, the highest risk of complications is noted - severe forms of ovarian hyperstimulation syndrome, multiple pregnancies. The use of GnRH antagonists is no less effective, but is not associated with a high risk of ovarian hyperstimulation syndrome.

[34]