1. Introduction

Infertile marriages have been growing rapidly: their frequency has increased from 10-15% to 25-30%, and there is no sign of a downward trend in the near future. The etiology of the disease is largely controversial, and new possible mechanisms of pathogenesis are discovered every year [1,2]. The results of research in recent decades have revealed that melatonin and changes in the biological rhythms of the body affect the development of the disease.

The main part of research on the mental pathology of female patients is dedicated to studying the prevalence of mood, neurotic and stress-related disorders. Infertile patients are more likely to experience anxiety and mood disorders than nulliparous women. The most commonly used psychometric methods include the Patient Health Questionnaire (PRIME-MD PHQ), the Hospital Anxiety and Depression Scale (HADS), the Beck Depression Inventory (BDI), and the 12-item Quality of Life Questionnaire (SF-12) [5].

Hormonal ovarian infertility is characterized by an imbalance of antioxidants and oxidants, which in turn leads to high levels of oxidative stress activity, even in women with normal body weight and no metabolic diseases. Oxidative stress underlies all physiological and pathological processes: aging, malignancy, inflammation, cardiovascular pathology. This affects tissue sensitivity to insulin and androgen levels and harms the female reproductive system [3,4].

One of the participants of the antioxidant system is melatonin, the main hormone of the pineal gland of all vertebrates.

The hormone controls the expression of luteinizing hormone (LG) mRNA, the production of apoptosis regulators Bcl2 and proteinase Casp3, the activity of insulin-like growth factor (IGF) and growth factor TGF-β, as well as LG receptors (Soares J., Masana M., Ersahin C., Dubocovich M. 2003). It is possible that melatonin enters the ovary from the bloodstream during follicular growth, and absorption of the hormone increases as follicles mature.

Melatonin is one of the most active regulators of oxidative balance today. However, the effects of exogenous melatonin have been studied in vitro or when administered to laboratory animals. There is a limited amount of work examining the effects of pineal hormone on redox processes in whole-body conditions. On the other hand, modern literature data shows the important role of impaired melatonin synthesis in the development of metabolic syndrome, and secondly, oxidative stress develops [6].

Thus, given the high prevalence of hormonal infertility and new information on the role of melatonin in folliculogenesis, there is a need to evaluate the role of this hormone in female reproductive function. The obtained results increase the effectiveness of treatment of patients with hormonal infertility and the ability to conceive using conservative therapy methods without the use of assisted reproductive technologies [1].

By implementing these tasks, it is possible to reduce infertility in women, strengthen reproductive health, and protect women's health in Uzbekistan.

2. The Purpose of the Study

Development of a method for determining female quality of life indicators and methods of melatonin use in the treatment of hormonal infertility while studying the quality of life and somnological disorders in patients with hormonal infertility.

3. Material and Methods

A total of 136 women of fertile age (18-42 years) were recruited for the planned research. The mean age of these women ranged from 24.6 to 30.2 years, corresponding to the study groups. All the women included in the research groups were residents of cities and villages of Khorezm region, 42.6% (n=58) of them lived in the city and 57.4% (n=78) lived in the countryside.

The examined contingent was divided into 2 groups: 1st group - group of women with hormonal infertility - 96 women; Group 2 - group of healthy women - 40 women.

The main group, in turn, was divided into 2 groups according to the cause of hormonal infertility: 1st group - women with external genital endometriosis, n=46; Group 2 - women with polycystic ovaries, n=50.

These groups were further divided into 2 subgroups depending on the type of treatment: 1-a-group treatment with dienogest in external genital endometriosis, n=20; In group 1b - use of melatonin combination with dienogest in the treatment of external genital endometriosis, n=26; 2-a-group - COC treatment of women with polycystic ovaries, n=24; Group 2b - women with polycystic ovaries were treated with combination of COC and melatonin (n=26).

In order to evaluate the quality of life of observed women, we used a scale developed by ourselves. This scale was constructed from several quality of life, sleep disturbance, and other pain scales that were most relevant to infertility.

When creating the scale, the Sleep Quality Index is from the Pittsburgh Questionnaire (PSQI); Questionnaire for evaluating the subjective characteristics of sleep according to Y. I. Levin; Women undergoing infertility treatment experience pain depending on the type of hormonal disorder, and it affects their quality of life. To assess this, we used the Visual Analogue Scale (VASH) as a basis for pain assessment. The HADS hospital scale was used to assess psychoemotional status. According to it, two types of psychoemotional states are assessed: anxiety and depression. From the scales presented above, the main indicators important in infertility were taken and summarized, and the following "Scale for evaluating the quality of life in women with infertility" was developed.

This scale assesses 19 indicators and consists of 3 main parts. In this, item 1-A describes sleep changes and disorders and consists of 7 questions.

Point 2-B- evaluates the psycho-emotional state of women and includes 8 questions.

Point 3-V consists of 4 questions characterizing pains in the pelvic region in women.

In this case, women fill out this questionnaire before and after treatment.

One of the most important indicators of women's infertility is the period of their visits to gynecologists. Analysis of the time of meeting women to these specialists according to the duration of infertility showed the following: 1 year 30.2±2.5% (n=29); 50±3.2% (n=48) from 1 year to 5 years; Women who applied more than 5 years ago (19.8±2.5%, n=19) for the purpose of consultation and/or diagnosis and treatment were practically close to each other (R>0.05).

136 women underwent medical examination in accordance with the specified tasks. Evaluation of hirsutism according to the Ferriman-Gallway scale gave the following results: 30 patients (22%) had mild hirsutism, 4 (2.9%) patients had moderate hirsutism, and 1 patient (0.73%) had severe hirsutism. The remaining women had no signs of body hair growth.

According to the ultrasound examination of the pelvic organs, out of 50 patients (100%) with polycystic ovaries in group 2, 32 patients (64%) had symptoms of bilateral ovarian enlargement, 13 patients (26%) - unilateral, 1 patient (2%) - the size of the ovaries did not exceed the norm. In total, several small follicles with a diameter of up to 10 mm in the amount of 12-15 pieces were identified in the structure of the ovaries. 27 patients (54%) had signs of uterine hypoplasia, possibly associated with irregular menstrual rhythm.

During the ultrasound examination of the group of women with external genital endometriosis in group 1, it was found that 39 out of 46 patients (84.8%) had endometrioid cysts in their ovaries. Among them, 14 (30.4%) had 2-sided and 25 (54.3) had 1-sided ovarian cyst damage. In the remaining 7 patients, the foci of endometriosis were suddenly detected in women undergoing diagnostic laparoscopy due to infertility.

The results of a comprehensive examination made it possible to divide patients according to phenotypes: classic (ultrasound signs of hyperandrogenism + polycystic ovaries + anovulation) - 29 people (58%), ovulatory (ultrasound signs of hyperandrogenism + polycystic ovaries) - 6 people (12%), androgen without (ultrasound + polycystic ovaries according to anovulation) - 15 (30%), anovulatory (hyperandrogenism symptoms + anovulation) - 10 people (2%).

In the course of this scientific work, women with external genital endometriosis and polycystic ovary syndrome were recruited from women with hormonal infertility, and the indicators of the quality of life of these women were studied and evaluated.

In the process of filling out the questionnaires, the respondents were asked to fill out a questionnaire before and after the treatment, which assesses the changes in their sleep, psycho-emotional state and the nature of their pain in the lower back region during the last month. The obtained results were evaluated in a point system. According to this, from 0 points to 38 points is normal; From 39 points to 57 points, subclinical and above 58 points indicate obvious changes in both psychoemotional and hormonal status, which are clearly expressed clinically. The results showed that when PCOS patients were asked to choose the main cause of sleep disturbance, the most common cause was stress (55%), followed by night or day work, night studying (29%), life events 10%, and sex. life was 6% - other reasons.

According to the results of the questionnaire for the assessment of subjective characteristics of sleep, patients with infertility were statistically significantly different from the control group in the level of pathological abnormalities (p = 0.004) - these disorders were more common in women with infertility.

The following features of the somnological profile of patients were revealed when distributed by phenotypes: deviations with the classical phenotype were present in 82.8% of cases, with ovulation - 16.7%, with non-androgenic - in 66.7%, and with anovulation - in 70% of cases. Although only the classic and ovulatory phenotypes were statistically significantly different (p = 0.004), this may indicate a more pronounced pathology of melatonin secretion in the classic phenotype, which is aggravated by sleep loss due to life circumstances, while the presence of ovulation reduces melatonin changes.

When we observed psychoemotional symptoms, the questioning using the scale of anxiety and depression did not reveal statistically significant differences between group 1 and group 2, which can be explained by changes in metabolic parameters affecting psychological status and high prevalence of infertility in both groups. In the carbohydrate metabolism study, fasting glucose levels were statistically significantly higher in group 2 compared to group 1, and both values were within the normal range. There was a statistically significant difference in glucose levels in the group of women with polycystic ovary syndrome compared to the other two groups.

In hormonal studies, there was a trend towards increased concentrations of luteinizing hormone (LG) in patients with PCOS, while follicle-stimulating hormone (FSG) values did not differ significantly between groups, and testosterone levels increased in the group of women with PCOS. AMH levels were statistically significantly higher in the PCOS group compared to controls. In group 1, due to endometriosis foci, high levels of estrogen in women's blood were noted, and antimuller's hormone was significantly lower compared to other groups.

Determination of melatonin and its metabolite in biological fluids. Patients with polycystic ovary syndrome are characterized by high levels of melatonin in blood, levels of 6-sulfatoxymelatonin in daily urine, and low concentrations of melatonin in follicular fluid. A decrease in the concentration of melatonin in the follicular fluid indicates a possible compensatory increase in the level of melatonin in the blood with an increase in the concentration of the same parameter in the blood. A decrease in the concentration of melatonin in the follicular fluid can lead to anovulation in women with polycystic ovary syndrome.

The result of melatonin deficiency in the ovary and its increase in the blood is also an increase in the amount of 6-sulfatoxymelatonin in the urine according to the principle of negative feedback.

4. Conclusions

1. In women with polycystic ovary syndrome and endometriosis, the concentration of melatonin in the follicular fluid was statistically significantly lower, compared to women in the control group, the level of melatonin in the blood and its metabolite in the urine remained unchanged, and there were no signs of anovulation. The highest levels of melatonin in the blood were found in the classic phenotype of polycystic ovary syndrome and endometriosis, and the lowest at ovulation, confirming the relationship between ovulatory dysfunction and melatonin levels in follicular fluid.

2. Sleep disturbance acts as an additional factor that distorts the metabolic profile of patients: deterioration of the somnological profile is associated with increased insulin resistance in patients with polycystic ovary syndrome.

3. In hormonal infertility, the development of anovulation is affected by the violation of the relationship between melatonin found in the blood and ovarian melatonin, as well as hyperandrogenism and an increase in the level of AMH (related to the level of melatonin in the blood). In the combined therapy of hormonal infertility, the synthetic analogue of melatonin allowed to increase the effectiveness of conservative therapy by 2.7 times and reduces the resistance to clomiphene during periods of ovulation stimulation.