OBJECTIVE

To evaluate the degree of pathogenetic disorders in patients with combined forms of infertility depending on the levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and morphologic picture of follicular fluid.

MATERIAL AND METHODS

31 patients with combined (uterine myoma and endomet-riosis) infertility factors were examined and made up 2 groups: the main group — 20 patients with a history of endometrial hyperplasia, the control group — 11 patients without endometrial hyperplasia. Intragroup comparative analysis was performed depending on the outcome of assisted reproductive technology (ART) programs: control group — positive outcome of ART-programs (n=6), main group — unsuccessful outcome of art (n=5). Intergroup analysis was performed depending on the pathogenetic causes of unsuccessful outcome: without endometrial hyperplasia in anamnesis — control group (n=11), with the presence of endometrial hyperplasia in anamnesis — main group (n=20). Clinical, anamnestic, instrumental and laboratory methods of examination were used for analysis. The level of TIMP-1 in follicular fluid was determined using kits with the measurement range of 0.06—10 ng/ml. Immuno-enzyme analysis was performed on an automatic tablet photometer multiskan FC (2012). Follicular fluid was investigated by the method of wedge dehydration.

RESULTS

The mean age of the patients was 33 [29; 36] years (p>0.05): with successful outcomes — 30 [30; 38] years, with unsuccessful outcomes — 36 [35; 36] years, with endometrial hyperplasia without atypia — 36 [32; 38] years. Patients without endometrial hyperplasia (control group) had primary infertility during from 2 to 5 years; in the main group, when combined with endometrial hyperplasia, secondary infertility was during from 5 to more than 10 years. The following was observed with the use of art technologies: protocol with gonadotropin-releasing hormone agonists was used in 22 (70.9%), protocol with gonadotropin-releasing hormone antagonists — in 9 (29.0%) of patients, IVF/ICSI technology — in 9 (29.0%) patients. Embryo transfer into the uterine cavity was performed in all pa-patients. There were no differences in morphologic evaluation of oocytes and embryos in intragroup comparison. In intergroup comparison, the qualitative and quantitative characteristics of oocytes and embryos were reduced. Pregnancy occurred in 6 (19.4%) women, and the number of live births was 6 children. There were no positive outcomes in patients with endometrial hyperplasia. In the study of the enzyme system in patients with combined forms of infertility, the level of matrix metalloproteinase-1 (MMP-1) was 1.3 [1.2; 1.6] ng/ml, confidence interval (CI) 1.5-2.2. The level of TIMP-1 in follicular fluid was 2400-2450 ng/ml in successful outcomes and 2550 [2550; 2775] ng/ml in unsuccessful outcomes, 95% CI 1015.1—4057.1 (p<0.01), reaching 2694 ng/ml or more in patients of the main group with endometrial hyperplasia. The study of follicular fluid by wedge dehydration method revealed the 3rd type (reactive) facies in patients without hyperplasia, and in patients with unsuccessful outcomes, the facies contained markers indicating impaired perfusion of the organ, pronounced ischemic-hypoxic manifestations, and the presence of a strained state of compensation. In patients with endometrial hyperplasia without atypia in anamnesis the 4th (chaotic) type of facies and markers indicating vascular elasticity disorder (endothelial dysfunction), angiospasm, markers of vascular sclerosis were detected. The presence of markers correlates with the level of TIMP-1 in follicular fluid (r=0.7). The higher the level of TIMP-1 (2694 ng/ml or more), the more markers indicating destructive changes in ovarian tissue, the less chance of pregnancy in ART programs.

CONCLUSION

Patients with combined factors of infertility (uterine myoma combined with endometriosis) at the age of 36 [32; 38] years old, with secondary infertility of more than 4 years, presence of pathological pregnancies with extragenital, gynecologic pathology (with hyperplastic processes in the endometrium in the anamnesis), surgical interventions on reproductive organs in the anamnesis (p<0.05) statistically significant increase in the level of TIMP-1 (2694 ng/ml and more) in follicular fluid, and markers indicating destructive changes in ovarian tissue (sclerosis of vessels, angiospasm and endothelial dysfunction), which reduces the chances of pregnancy in ART programs.