RU2625723C1 - Method of pre-clinical diagnostics of premature of ovarians in women of reproductive age - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: for preclinical diagnosis of premature ovarian depletion in women of reproductive age in transvaginal ultrasound examination of the ovaries, anthral follicles are counted on the 5th-7th day of the menstrual cycle, and in determining the total number of antral follicles in both ovaries 6 and less, an additional AMG immunoassay and calculate the coefficient P=(F*G): V, where P is the coefficient of premature ovarian depletion, F is the number of antral follicles, G is the concentration AMG in serum in absolute units, V is the age of a woman in years, and when P is 0.33 or less, early ovarian depletion is diagnosed and the patient is transferred to reproductive canters for ART programs.

EFFECT: method allows to identify young women, threatened by premature ovarian exhaustion, at the preclinical stage, to eliminate unjustified medicamentous effect on the patient's organism with the absence of the prospect of natural conception while reducing the costs of infertility treatment.

4 ex

Description

The invention relates to medicine, namely to gynecology and reproductology, and can be used to determine indications for assisted reproductive technology (ART) programs in women of reproductive age, threatened by premature ovarian exhaustion.

The current demographic situation is characterized by low reproductive potential and “aging” of a group of women of young fertile age, which does not allow predicting an increase in fertility (Padrul M.M. et al., 2014).

The physiology of aging of the reproductive system in men and women is fundamentally different. In men, reproductive function persists until death and corresponds to physiological old age, and its attenuation fully corresponds to the aging of other organs and systems. At the same time, in women, disabling reproductive function does not correspond to aging of other organs and systems (Sampson N, 2007, Fish N., 2009, Boyarsky K.Yu., Gaidukov S.N., 2011). The Dutch researcher E. te Velde (2002) analyzed the differences in the time of the beginning of a decrease in the ability to conceive, the time of the end of the ability to conceive, the beginning of irregular menstruation and menopause. The author concludes that the reproductive system is switched off 7-8 years before menopause and 3-4 years before the onset of menstrual irregularities. In studies by Rishardson SJ. et al. (1987), attention was drawn to the fact that in one woman out of 1000 menstruation ceases for an unknown reason at 30, while in such a woman the ability to conceive is lost at 22. Also, according to the authors, in one woman out of 100 menopause occurs at 40, and in such a woman the physiological time of the last birth is 32 years.

A significant aggravation of the demographic situation, a decrease in the reproductive potential and premature aging of a group of women of young fertile age can be judged by the data cited in the studies of Padrul M.M. et al. (2014). In a group of girls aged 15-19 years, 3% of the examined authors identified laboratory criteria for premature ovarian exhaustion, and in the group of 20-24 years old, the proportion increased to 7%. Summarizing the data of the researchers, it is easy to see that over the past 27 years (from 1987 to 2014) premature ovarian aging in women of young fertile age began to be recorded 30-70 times more often.

It is known that the mechanism of disabling reproductive function in women is ovarian in nature, and menopause occurs when the follicular reserve (ovarian reserve) in the ovaries is depleted (Toner J.P., 1991). Despite a significant breakthrough in the study of ovarian aging processes, a number of theoretical gaps remain in the fundamental knowledge on this issue. In 2011, a working group of experts from 5 leading countries of the world (STRAW), studying the stages of aging of the reproductive system, showed the need for additional research and the development of modern biomarkers that reflect the staged formation of premature ovarian failure. In the study of various factors of ovarian aging, such as the level of anti-Muller hormone (AMH), the number of antral follicles, basal levels of FSH, inhibin B and estradiol, it was found that a decrease in AMH is the earliest and most reliable indicator of ovarian reserve.

Anti-Muller Hormone (AMH) is also an essential indicator of the aging of the female reproductive system. This is due to the fact that this ovarian non-steroidal hormone can be produced only by follicle granulosa cells from the preantral stage to the large antrum stage. In the ovaries of a girl, the first signs of AMH production appear in the prenatal period (in utero at 32-36 weeks of pregnancy) and the level of this hormone in the blood slowly rises with age. The maximum level of AMH reaches a woman aged 20-30 years, after which it gradually decreases and by menopause is zero. Van Rooij et al. (2005) in a group of women aged 26–40 years, they studied changes in such indicators of ovarian aging as the number of antral follicles (ChAF), the level of AMH, basal levels of FSH, inhibin B and estradiol twice, with intervals of 4 years. It turned out that in women, the level of AMH and PFA had a correlation with age, while basal levels of FSH and inhibin B had such a correlation only in patients after 40 years, and the level of estradiol did not have such a correlation at all. According to these authors, a decrease in the level of AMH is the best indicator of ovarian aging, the second after it is a decrease in PFA. Basal levels of FSH and inhibin are indicators of moderate ovarian aging, and estradiol levels are considered irrelevant. The results of these studies fully coincide with the conclusion of the European Society for Human Reproduction and Embryology (Bologna criteria) that the most reliable and accurate indicators of ovarian reserve are the level of AMH and the number of antral follicles (Ferraretti A.P. et al., 2011).

Hale G et al. (2007) studied in detail the levels of hormones in the blood of patients according to the STRAW classification. It turned out that the earliest marker showing the transition from the peak of reproductive function to the late reproductive period is a 10-fold drop in AMH level. At the same time, indicators such as an increase in the basal level of FSH, a decrease in the basal level of inhibin B are much less pronounced, and the level of progesterone in the middle of the luteal phase of the cycle remains unchanged. The authors conclude that the role of AMH as a promising marker in assessing a decrease in a woman's reproductive function with age. In addition, the researchers established the fact that with the onset of menopause, a further drop in the level of AMH is noted. In the early and late period of transition to menopause, the level of this hormone is 0.15 + 0.2 and 0.06 + 0.08 ng / ml, respectively. In postmenopausal women, the level of this hormone is zero. The authors draw conclusions about AMH as the most sensitive marker of ovarian aging in humans.

In connection with the clinical use of the level of AMH as a promising marker of a decrease in the reproductive function of women, the question arose about the normal values of this hormone in women of various age groups with preserved ovarian reserve and premature ovarian depletion.

The causes of premature “aging” of the reproductive system remain a subject of discussion, however, it remains important to identify this process early (before the pre- and menopause) in women of young and middle reproductive age in order to determine the optimal tactics for managing such women in terms of implementing their reproductive tasks.

From the analysis of scientific, medical and patent literature, we have identified the following technical solutions.

A known model created by a group of Dutch authors based on a population-based study that can predict the possible time of onset of menopause by a single measurement of AMH. So, according to the authors, if a woman at 37 years old has a low level of AMH = 0.3 ng / ml, then the time of onset of menopause in such a woman is 41-44 years, which is 7-10 years earlier than in the population ( 51 years old). Conversely, if a woman at 42 years old has a high level of AMH = 2 ng / ml, then the onset of menopause in this woman should be 51-53 years, which is 2 years later than the average in the population (Van Disseldorf J. Faddy MJ, Themmen AP Relationship of serum antimullerian hormone concentranion to age at menopause / J. Clin. Endocrinol. Metab. - 2008. - Vol. 93 (6). - P. 2129-2134).

The disadvantages of this technical solution are:

1. Clarification of the time of menopause in women of late reproductive age, which makes it impossible to isolate from the general population of women of young and middle reproductive age threatened by premature ovarian exhaustion with unrealized reproductive function.

2. The lack of the possibility of timely ART programs until critical indicators are reached, indicating a decrease in the functional parameters of the ovaries characteristic of menopause.

3. It does not allow to select patients who are threatened by premature ovarian exhaustion.

A known method of selecting patients with a weak response syndrome of ovaries in need of transfer to a treatment program using donor oocytes (RF Patent No. 2,565,449, 10/20/2015), by examining blood hormones, characterized in that the patient has the 2nd-3rd the days of the menstrual cycle preceding gonadotropic stimulation examine the level of anti-Muller hormone (AMH) in the blood serum and, if the level of AMH is 0.1-0.5 ng / ml, the concentration of follicle-stimulating hormone (FSH), expressed in mIU / ml, is additionally determined counting the FSH / AMH ratio is established and, if the value of the obtained ratio is equal to or exceeds 51, the treatment is adjusted and the patient is transferred to the treatment program using donor oocytes.

The disadvantages of this technical solution are:

1. Inclusion of patients in ART protocols with diagnosed infertility, while the purpose of the study at the preclinical stage is to identify a group of women who are threatened with premature ovarian exhaustion.

2. The method was developed for patients with a “weak” response of the ovaries to gonadotropic stimulation.

3. The method involves the use of donor oocytes, while our approach allows us to identify women who are threatened by premature ovarian exhaustion at the preclinical stage to realize the possibility of solving reproductive problems using their own oocytes.

A known method for predicting ovulatory menstrual cycles in women with primary oligomenorrhea in the anamnesis (Patent RF №2 549 985, 05/10/2015), characterized by the study of the content of antimuller hormone (AMH) in blood serum for 3-5 days of the menstrual cycle by the enzyme immunoassay and the number of antral follicles with a diameter of 2-5 mm on the 5-7 day of the menstrual cycle by transvaginal ultrasound, predicting ovulatory menstrual cycles with an AMH content of 5.0 to 8.0 ng / ml and the number of antral follicles in the ovaries about 10.

The disadvantages of this technical solution are:

1. The method was developed for patients with clinical manifestations of ovarian dysfunction and menstrual irregularities (primary oligomenorrhea), which is most often recorded, on the contrary, in women with polycystic ovary syndrome (with a large number of antral follicles and high levels of AMH, with a high frequency of anovulatory menstrual cycles )

2. The method is designed to highlight a group of patients who may expect spontaneous ovulatory menstrual cycles with a high ovarian reserve (high level of AMH, a large number of antral follicles) and a high risk of atresia of antral follicles, typical for women with primary oligomenorrhea.

3. The method cannot be proposed for women who are threatened with premature ovarian exhaustion.

Closest to the claimed technical solution is the method by which to evaluate the ovarian reserve a hormonal examination is carried out on the 2-3 day of the cycle (LH, FSH, estradiol, AMG) and ultrasound examination of the pelvic organs. FSH values from 3 to 8 IU / L suggest a good ovarian reserve and an adequate ovarian response to stimulation in the IVF program. An increase in FSH may be a predictor of a “weak” response. In some cases, in young women, against the background of normal FSH values, a hidden decrease in the ovarian reserve is possible, which is detected only by a low level of AMH. Another criterion for ovarian reserve is the volume of the ovaries and the number of follicles, determined by ultrasound on the 2nd-4th day of the cycle. The presence of less than 5 follicles with a diameter of up to 10 mm is regarded as an indirect sign of reduced ovarian reserve. Thus, a weak response to stimulation can be assumed in the following cases: patient over 37 years old; the level of FSH for 2-3 days of a cycle of more than 10 IU / l; the number of antral follicles with ultrasound on 2-4 days of the cycle is less than 5; AMH level <1 ng / ml ("Weak" answer in IVF programs: a modern look at the problem. Source: http://www.babyplan.ru/biblioteka/_/eko/slabyj-otvet-v-programmah-eko-sovremennyj -vzglyad-na-problemu # ixzz4G5outsvh \ February 27, 2013 \).

The disadvantages of this technical solution are:

1. The method is designed to assess the ovarian reserve in infertile women planning ART programs, which excludes the possibility of identifying a group that is threatened by premature ovarian exhaustion from the general population of women of reproductive age.

2. It does not allow at the preclinical stage to select patients who are threatened by premature ovarian exhaustion.

3. The method is proposed for patients over 37 years old and cannot be recommended for women of young and middle reproductive age.

The task to which the claimed invention is directed is to obtain an early prognostic and diagnostic marker that allows women of young and middle reproductive age to be allocated a group of patients who are threatened by premature ovarian exhaustion to clinical signs of a decrease in their functional activity.

The problem is solved by the proposed method for preclinical diagnosis of premature ovarian exhaustion in women of reproductive age, including ultrasound examination of the ovaries and determination of the level of antimuller hormone (AMH) in the blood serum, characterized in that during ultrasound examination of the ovaries for 5-7 days of the menstrual cycle, antral follicles are counted , in identifying the total number of antral follicles in both ovaries of 6 or less, an AM study is additionally prescribed G and calculate the coefficient P, calculated as the ratio of F (the number of antral follicles) x G (concentration of AMG in absolute units), to V (woman's age in years). Upon receipt of a P value of 0.33 or less, premature ovarian exhaustion is diagnosed.

The technical result provided by the given set of signs is the early identification of women who are threatened by premature ovarian exhaustion, as well as cost reduction due to the fact that the proposed coefficient allows reproductologists to recommend a specific category of women in a timely manner (up to 30 years old with no indications of previous surgery ovaries) with a coefficient of P below 0.33 to abandon contraception for the early implementation of natural conception.

The choice of the studied characteristics is not random. Numerous studies indicate that the level of AMH and the number of antral follicles are the most reliable indicators of ovarian reserve. In addition, the level of AMH and CHAF correlate with age in all women of the reproductive period and the menopause period (O.V. Bulavenko, 2011). It is known that the lower the levels of AMH, the smaller the number of antral follicles and the older the woman's age, the more pronounced a decrease in ovarian reserve. Important is the fact that the level of AMH is not affected by pregnancy, lactation, taking combined oral contraceptives, anovulatory menstrual cycles, the day of the menstrual cycle. It is proved that a decrease in AMH level is the best indicator of ovarian aging, the second after it is a decrease in ChAP. The determination of the minimum threshold value of antral follicles (6) is also not random. In accordance with the Bologna criteria (ESHRE Unified Opinion - European Society for Human Reproduction and Embryology) on the question of determining the “poor response” of the ovaries to stimulation in in vitro fertilization cycles) (Ferraretti A.P. et al., 2011), it was found that the deviation of the results test for ovarian reserve is recorded when the number of antral follicles <5-7 (less than 7 is 6 or less). In contrast to studies by Van Rooij et al. (2005) our own studies have shown that not all women 20-30 years old have AMH concentrations that reach their maximum values. In 8.8% of patients from 26 to 30 years old, a significant, uncharacteristic for women of young and middle age, decrease in the concentration of AMH and, accordingly, ovarian reserve was registered for the first time.

Our own studies conducted by us from 2013 to 2015 were devoted to studying the level of AMH in women of various age groups. The study included 960 women aged 20 to 49 years. In the group of women aged 20–25 years (n = 54), 51.9% recorded AMH levels of 5 to 10 ng / ml, 5.6% had AMH values higher than 10 ng / ml, and the remaining 42.6% - serum concentration of AMH was in the range from 1 to 5 ng / ml. In the group of women 26-30 years old (n = 274), AMH levels of less than 1 ng / ml were first recorded in 8.8% of the subjects. For most women in this group (53.3%), the content of the studied indicator ranged from 1 to 5 ng / ml, in 33.9% - from 5-10 ng / ml. The proportion of patients with an AMH level of more than 10 ng / ml decreased to 4%. When analyzing the age group of 31-35 years (n = 343), it was found that the level of AMH from 1-5 ng / ml was recorded in the vast majority of women (61.2%), the proportion of patients with AMH was 5-10 ng / ml or more 10 ng / ml continued to decrease progressively compared to younger women and amounted to 21.3% and 2.9%, respectively, while the number of women with low AMH concentrations (<1 ng / ml), on the contrary, increased to 14, 6% A similar situation was recorded in subjects 36–40 years old (n = 232). In this group, a further decrease in the proportion of women with AMH levels from 1-5 ng / ml, from 5-10 ng / ml and more than 10 ng / ml, respectively, to 56.5%, 16.4% and 0.4%, was noted. while the number of subjects with an AMH content of less than 1 ng / ml increased to 26.7%. In patients 41-45 years old (n = 47), for the first time, there was no registration of AMH values of more than 10 ng / ml, while almost half (42.6%) of the studied hormone concentration was in the range up to 1 ng / ml, in 53.2% - from 1-5 ng / ml. The proportion of patients with an AMH content of 5-10 ng / ml was 4.3%. In all 10 patients of the most age group - over 46 years of age, AMH values were in the lower limits - from 0-1 ng / ml.

At the next stage of our studies, we compared the data on PFA with different levels of AMH (0-1 ng / ml; 1-5 ng / ml; 5-10 ng / ml; more than 10 ng / ml) in women of different age groups. A relationship was found between the number of antral follicles and the level of AMH, regardless of the age of the patients. So, at an AMH level of 0-1 ng / ml, 2 to 6 antral follicles were recorded, at an AMH concentration of 1-5 ng / ml, from 5 to 12 follicles, with an AMH content of 5-10 ng / ml, from 8 up to 14 follicles, with indices of more than 10 ng / ml - from 12 to 20. An interesting fact was that higher values of AMH corresponded to a greater number of antral follicles, and, conversely, at low AMH levels, a smaller number of antral follicles was recorded. This feature was established in all age groups. The data obtained suggest that the combination of parameters of the PAF and the level of AMH with greater diagnostic value than age allows us to estimate the ovarian reserve of a woman. Our further studies were aimed at finding a coefficient that allowed us to determine the ovarian reserve for a particular patient and lower boundaries indicating the risk of premature ovarian exhaustion by the number of antral follicles and the level of AMH, as well as taking into account age. Empirically, we deduced the coefficient P = (F * G): V, where F is the number of antral follicles, G is the concentration of AMH in serum in absolute units, V is the woman's age in years.

A detailed description of the method and examples of its clinical implementation

The method is as follows. In women of young and middle reproductive age, who applied to antenatal clinics, family planning centers, reproduction centers with various problems (preventive examination, pregnancy planning, contraceptive consultation, with genital inflammation, absence of children in marriage, etc.) at 5- During the transvaginal ultrasound examination of the ovaries, the 7 days of the menstrual cycle count the antral follicles, when the total number of antral follicles in both ovaries is revealed 6 and less, an additional AMG level study is prescribed.

Transvaginal ultrasonographic examination of the pelvic organs and ovaries is carried out on the apparatus "AlokaprosaundSSD - 3500 SX" (Japan) for 5-7 days of the menstrual cycle. Counting antral follicles (from 2 to 6 mm) is performed in each ovary, after which the result is summarized. If the total number of antral follicles in both ovaries is 6 or less, a study of the level of AMH by an enzyme-linked immunosorbent assay is additionally prescribed.

The determination of the content of antimuller hormone in blood serum is carried out using the enzyme immunoassay kit AMHGenIIELISA (BeckmanCoulter Inc., USA). Blood sampling is carried out in the morning on an empty stomach from the cubital vein.

The definition of AMG is based on the principle of enzyme-enhanced “two-stage” sandwich control. During the analysis, the standards, control and patient samples were incubated in microplate cells coated with anti-Muller hormone antibodies. After incubation and washing, the cells were treated with biotinylated anti-Muller hormone antibodies. After the second incubation and subsequent washing, streptavidin conjugated with horseradish peroxidase was added. After the third incubation and subsequent washing, the cells were incubated with a substrate of a horseradish solution. Then a stop solution was added and the amount of converted substrate enzyme was determined by measuring the optical density at wavelengths of 450 and between 600 and 630 nm. The measured absorption is directly proportional to the concentration of the antimuller hormone present. A set of standards of antimüller hormone was used to construct a standard absorption curve, from which it was possible to calculate its unknown concentrations in the studied samples.

When obtaining quantitative values of the total number of antral follicles in both ovaries and the level of AMG, the coefficient P = (F * G) is calculated: V, where F is the number of antral follicles, G is the concentration of AMG in blood serum in absolute units, V is the woman's age in years (take into account the number of full years at the date of study). Upon receipt of a P value of 0.33 or less, premature ovarian exhaustion is diagnosed and the patient is transferred to reproduction centers for ART.

Thus, the technique allows for the timely formation of understanding and accelerate the implementation of reproductive and reproductive functions in women, for which issues of delayed reproduction for social, material, and other reasons may result in the need to use donor oocytes, which will entail significant material losses and moral experiences.

The performance of the proposed method is confirmed by the following clinical examples:

Example 1

Patient An, 31 years old (V = 31), in November 2013 contacted Center for Human Reproduction and IVF LLC with complaints of primary infertility for 5 years. From the anamnesis, it is known that in childhood the patient suffered rubella, Hepatitis A. In 2011, the patient underwent laparoscopy and chromohydrotubation for the left-side hydrosalpine (the right fallopian tube is passable, the left is represented by the hydrosalpinx). Salpingoneostomy on the left was performed with restoration of patency of the fallopian tube. Menstrual cycle from 13 years. Menstruation is regular after 26-28 days for 5 days, with dark smeared discharge before and after menstruation.

The patient is married for 5 years.

Infectious status of both spouses without features.

As part of the examination, the patient was asked to evaluate ovarian reserve using transvaginal ultrasound. When conducting a transvaginal study on the 5th day of the MC (11/03/2013), 3 antral follicles were recorded in the right ovary and 2 antral follicles in the left (F = 5). It was proposed to investigate the level of AMH. The content of AMG in the patient's blood serum from November 3, 2013 was equal to 0.78 ng / ml (G = 0.78).

Based on the obtained values, the coefficient P = (F * G): V was calculated. P = (5 × 0.78): 31 = 0.13, which made it possible to predict premature ovarian exhaustion in this patient and substantiated the need for urgent solution of reproductive and reproductive problems using ART programs.

In January 2014, the patient was included in the stimulation protocol for the ART program. Against the background of hormonal stimulation using gonadotropins in combination with gonadotropin-releasing hormone antagonists, 3 dominant follicles were registered. On January 27, 2014, follicle puncture was performed, 3 oocytes were aspirated. As a result of fertilization, 2 embryos were obtained. 01/30/2014 2 embryos were transferred to the uterine cavity. On February 13, 2014, a pregnancy ended in childbirth was registered.

In January 2016, the patient returned again (13 months after the birth of the baby and 11 months after the cessation of lactation) due to the absence of menstruation for the last 3 months. During the examination, premature menopause was established, hormone replacement therapy was prescribed.

Example 2

Patient M-va, 27 years old (V = 27), in August 2013 contacted Center for Human Reproduction and IVF LLC with complaints of miscarriage.

From the anamnesis it is known that I didn’t get sick with childhood infections, I didn’t tolerate sexually transmitted infections, I have denied the common diseases and surgical interventions. In 2011, a non-developing pregnancy of a short period was established, curettage of the uterus was made. Menstrual cycle from 16 years. Menstruation is regular after 26 days for 3 days.

The patient is married for 6 years, she is currently planning children, but uses contraceptive methods (condom) to clarify the causes of an unsuccessful pregnancy.

Infectious status of both spouses without features.

As part of the examination, the patient was asked to evaluate ovarian reserve using transvaginal ultrasound. When conducting a transvaginal study on the 6th day of the MC (08.16.2013), 3 antral follicles were recorded in the right ovary and 3 antral follicles in the left (F = 6). Additionally investigated the level of AMH. The content of AMG in the patient's blood serum from 08.16.2013 is 1.7 ng / ml (G = 1.7).

Based on the obtained values, the coefficient P = (F * G): V was calculated. P = (6 × 1.7): 27 = 0.38, which allowed the patient to be excluded from the group of women who are threatened by premature ovarian exhaustion. Upon further examination, the spouse revealed deviations in the spermogram, andrologist prescribed treatment. November 7, 2015, a clinical pregnancy was diagnosed, which ended in childbirth in 36-37 weeks.

Example 3

Patient Fs, 28 years old (V = 28), in July 2015, turned to Center for Human Reproduction and IVF LLC for the purpose of pregravid preparation.

From the anamnesis it is known that in childhood the patient suffered from chickenpox, in 2008 he was diagnosed with ureaplasmosis, chlamydia, a viral infection (Epstein-Barr virus) (treatment was carried out with control of cure). Surgery denied. Menstrual cycle from 14 years. Menstruation is regular after 28 days for 5 days.

The patient is married for 5 years, currently planning children, does not use contraceptive methods (before planning pregnancy, she took combined oral contraceptives).

Infectious status of both spouses without features.

As part of the examination, the patient was asked to evaluate ovarian reserve using transvaginal ultrasound. When conducting a transvaginal study on day 5 of the MC (08/13/2015), 4 antral follicles were recorded in the right ovary and 2 antral follicles in the left ovary (F = 6). Additionally investigated the level of AMH. The content of AMG in the patient's blood serum from 08/13/2015 is 1.37 ng / ml (G = 1.37).

Based on the obtained values, the coefficient P = (F * G): V was calculated. P = (6 × 1.37): 28 = 0.29, which made it possible to predict premature ovarian exhaustion in this patient and substantiated the need for urgent solution of reproductive and reproductive problems using ART programs. The patient reapplied after 1 year for the ART program because of the lack of natural conception within 1 year.

Example 4

Patient V-va, 30 years old (V = 30), in April 2016 contacted Center for Human Reproduction and IVF LLC with complaints of pain in the lower abdomen, copious discharge from the genital tract that appeared during the last month.

From the anamnesis it is known that in childhood the patient suffered from chickenpox, in 2011 he was diagnosed with ureaplasmosis, bacterial vaginosis (treatment was carried out with control of cure). Surgery denied. Menstrual cycle from 13 years. Menstruation is regular after 25 days for 5 days. Recently (since 2015) - menstruation in 21-23 days for 3 days. The patient is married for 2.5 years, does not currently plan children, uses barrier methods of contraception (condom).

At the stage of examination of the infectious status, the patient revealed ureaplasmosis, cytomegalovirus infection. The spouse is also diagnosed with ureaplasmosis, a cytomegalovirus infection.

After anti-inflammatory treatment and healing (according to the results of control tests and clinical improvement), the patient was asked to evaluate the ovarian reserve using transvaginal ultrasound. When conducting a transvaginal study on the 7th day of the MC (06/10/2016), 2 antral follicles were recorded in the right ovary and 2 antral follicles in the left ovary (F = 4). Additionally investigated the level of AMH. The content of AMG in the patient's blood serum from 10.06.2016 is 0.86 ng / ml (G = 0.86).

Based on the obtained values, the coefficient P = (F * G): V was determined. P = (4 × 0.86): 30 = 0.11, which made it possible to predict premature ovarian exhaustion in this patient and substantiated the need for urgent solution of reproductive and reproductive problems using ART programs.

An analysis of the data presented allowed us to propose a coefficient as an estimate of the reserve capacity of the ovaries and the allocation of a group of women of reproductive age who are threatened by premature ovarian exhaustion for timely resolution of reproductive and reproductive problems.

Thus, the claimed method allows you to:

- at the preclinical stage, identify patients of reproductive age who are threatened by premature ovarian exhaustion, especially among young women;

- determine the objective indications for ART using “donor" oocytes;

- timely correct tactics for treating women who are threatened with premature ovarian exhaustion, eliminate unreasonable drug effects on the patient’s body with no prospect of natural conception;

- reduce the cost of infertility treatment, including the use of donor oocytes in ART programs, as well as moral distress, unreasonable expectations;

- immediately recommend to women at risk of premature ovarian exhaustion consultations in reproduction centers;

- bring objective information to women who are threatened with premature ovarian exhaustion about the urgent need for reproductive and reproductive tasks using ART programs in order to use their own oocytes;

- help socially active women formulate life priorities.

The inventive method for preclinical diagnosis of premature ovarian exhaustion in women of reproductive age has been tested on a large number of patients, has shown high efficiency in use and can be recommended for wide clinical use in antenatal clinics, gynecological departments, family planning centers, reproduction centers.

Claims (1)

A method for the preclinical diagnosis of premature ovarian exhaustion in women of reproductive age, including ultrasound examination of the ovaries and determination of the level of antimuller hormone (AMH) in the blood serum, characterized in that when transvaginal ultrasound examination of the ovaries on the 5-7th day of the menstrual cycle, antral follicles are counted, if any the total number of antral follicles in both ovaries of 6 or less is additionally prescribed a study of the level of AMH by the enzyme immunoassay and based on the data obtained, the coefficient P = (F * G) is calculated: V, where P is the coefficient of premature ovarian exhaustion, F is the number of antral follicles, G is the concentration of AMH in blood serum in absolute units, V is the woman's age in years, at receiving a P value of 0.33 or less, diagnose premature ovarian exhaustion and transfer the patient to reproduction centers for ART.