Clinicocytological Characteristics of Decidualizing Endometrium in First-Trimester Pregnancy Loss

The dissertation is devoted to the clinicocytological study of the decidualizing endometrium in processes of implantation and placental development in first-trimester pregnancy loss. The research is aimed at evaluating the proliferative activity, cellular differentiation, and programmed cell death of decidual tissue cells depending on the localization of the embryo in the uterine wall, as well as analyzing serum levels of sex hormones and prolactin. The work makes it possible to identify the leading factors influencing pregnancy continuation and to substantiate approaches to early pathogenetic therapy.

Pregnancy loss is one of the leading problems in modern obstetrics. Among clinically diagnosed pregnancies, its frequency reaches 25%, with first-trimester losses accounting for 50% to 80% of all losses (E.F. Kira et al., 1999; E.L. Boyko et al., 2002; V.N. Serov, 1997; A.N. Strizhakov, 1997; Zinaman, 1996). Despite the enormous efforts of clinicians, the frequency of pregnancy termination at various gestational ages, having decreased to a certain level, has remained constant for a long time and does not depend on the successes of pharmacotherapy.

The initiating mechanisms of pregnancy loss may take multiform shapes, depending on the morphofunctional state of various systems of the maternal organism and the ovum (M.V. Fedorova, E.P. Kalashnikova, 1986; V.M. Mikhailov et al., 1992; E.F. Kira, Yu.V. Tsvelyov, V.F. Bezhenar, 1999).

Etiological factors and pathogenetic mechanisms of pregnancy loss undergo transformation in accordance with changes in the environment and conditions of human existence. The polyetiological symptom complex of pregnancy loss may be regarded as a manifestation of the imbalance in the coexistence of the reproductive system and other, primarily vital, systems of the organism (M.V. Fedorova, E.P. Kalashnikova, 1986; E.F. Kira et al., 1999). Therefore, numerous studies on the problem of pregnancy loss, both outside and during pregnancy, as a rule, reveal in them various disturbances, often of an opposite nature.

The contradictory nature of research results on the problem of pregnancy loss stimulates further search at higher technical and methodological levels.

Diverse disturbances in the functioning of certain systems of the female organism responsible for reproductive health and ensuring normal development of the fertilized ovum manifest their effect at the local level in the endometrium, and changes in it may persist in the non-pregnant state. The availability of modern opportunities for studying at the cellular and molecular levels the processes occurring in the endometrium upon the onset of pregnancy constitutes a new stage in the study of this problem.

The survival of the "allogeneic fetus" in the maternal organism is ensured by a complex of anatomical, hormonal, and immunological mechanisms, the majority of which operate at the level of the uteroplacental barrier.

One of the system-forming factors ensuring physiological course of pregnancy is the formation of a specific transient population of decidual cells of the endometrium, unique in terms of proliferation, differentiation, and cell death. In the processes of cytodifferentiation, proliferation, and programmed death of decidual cells, hormonal, infectious, genetic, and other factors play a role.

The success of implantation depends on the interaction of the ovum with the uterine epithelium and the readiness of the endometrium. Endometrial readiness includes the degree of development of spiral arteries and the proliferative activity of the endometrium. These processes determine the formation of a full-term uteroplacental complex during the periods of implantation and placental development, which ensures the constant supply of maternal arterial blood to the placental barrier of the villi. Inadequate formation of the placenta, uteroplacental blood flow, may be the cause of spontaneous pregnancy termination, placental insufficiency, gestosis, fetal developmental delay, and intrauterine fetal infection (I.N. Ozhiganova, 1994; R.I. Shalina, 1995; M.V. Medvedev, E.V. Yudina, 1998, 2000; O.B. Panina, 2000; I.S. Sidorova, I.O. Makarov, 2004; A.N. Strizhakov et al., 2000, 2001; O.F. Serova, A.P. Milovanov, 2001).

Advances in cell and tissue culture technology have made it possible to proceed to the analysis of the development of decidualizing endometrial cell populations in vitro. However, the question of changes in the processes of proliferation and cell death of the endometrium in connection with implantation and placental development in physiological pregnancy and pregnancy loss in vivo has not received sufficient attention in the modern literature. The relevance of studying endometrial cell proliferation and cell death (apoptosis) is great, since endometrial cells constitute a growing population. However, during pregnancy, differentiated decidual cells apposed to the trophoblast die, which allows one to regard the population of decidual cells as a self-renewing type (Johannison, 1993). Therefore, it is important to study the ratio of proliferation and death processes at each stage of decidual tissue cell function. In this regard, studies that help clarify the role of these processes depending on the site of ovum localization during the period of implantation and placental development in physiological pregnancy and pregnancy loss appear to be highly relevant and contemporary.

The aim of the work — Clinicocytological evaluation of the decidualizing endometrium in processes of implantation and placental development in pregnancy loss. The research tasks:

1. To characterize the features of somatic and gynecological anamnesis in women with pregnancy loss.

2. To conduct a cytological evaluation of the decidualizing endometrium depending on the site of embryo localization in physiological first-trimester pregnancy in processes of implantation and placental development.

3. To study the proliferative activity, processes of cellular differentiation, and programmed cell death (apoptosis) of decidualizing endometrium cells in order to determine compensatory capabilities in pregnancy loss.

4. To determine the levels of serum sex hormones and prolactin depending on the site of embryo localization in processes of implantation and placental development in physiological pregnancy and first-trimester pregnancy loss.

The dissertation was carried out in accordance with the main plan of research works of the Department of Obstetrics, Gynecology and Perinatology of the Saint Petersburg State Medical Academy named after I.I. Mechnikov, at the gynecological department of SPb GUZ MSC 18. Cytological studies were conducted in the Laboratory of Cell Morphology of the Institute of Cytology of the Russian Academy of Sciences.

Scientific novelty and significance of the work.

A clinicocytological evaluation of the state of the decidualizing endometrium in physiological pregnancy and pregnancy loss in the first trimester has been conducted, depending on the localization of the embryo in the uterine wall during implantation and placental development.

For the cytological characterization of the decidualizing endometrium, strictly orientation-directed endometrial scrapings obtained as a result of artificial abortion surgery and curettage of the uterine cavity during spontaneous abortion have been used for the first time.

It has been established that embryo implantation into the mucous membrane of the anterior uterine wall is an unfavorable prognostic criterion for pregnancy continuation. Implantation into the mucous membrane of the posterior uterine wall is optimal in connection with the pre-readiness of the decidualizing endometrium. A high level of proliferative activity and cellular differentiation and a low level of cell death of the decidualizing endometrium upon embryo implantation into the mucous membrane of the posterior uterine wall determine the formation of a full-term uteroplacental circulation.

On the basis of a comprehensive study of clinical, hormonal, and cytological risk factors of pregnancy loss, it has been established that the leading factors influencing pregnancy continuation in the first trimester are: the site of embryo localization, proliferative potential, the degree of morphofunctional differentiation and programmed cell death (apoptosis) of the decidualizing endometrial cell population, serum levels of sex steroids and prolactin, as well as the absence of an infectious agent.

The work demonstrates that in physiological pregnancy and pregnancy loss, depending on the localization of the embryo in the uterine mucous membrane, various processes occur that are associated with changes in proliferative activity, cellular differentiation, and programmed cell death of decidualizing endometrium cells. Mechanisms of compensatory reactions of decidualizing endometrium cells for pregnancy development under conditions of inadequate uteroplacental circulation in pregnancy loss have been identified.

For the first time, the relationship between the site of embryo implantation and changes in serum levels of progesterone, estradiol, testosterone, and prolactin has been determined. It has been found that the morphofunctional insufficiency of the decidual base of the endometrium is based on hormonal disturbances that affect proliferative activity, cytodifferentiation, and the apoptosis index of the decidualizing endometrial cell population. The predominant role in these processes belongs to the hormones estradiol, progesterone, and prolactin.

Practical significance.

The conducted research expand the understanding of cellular mechanisms of spontaneous pregnancy termination and explain the necessity of early pathogenetic therapy of pregnancy loss.

Upon diagnosing embryo implantation into the mucous membrane of the anterior uterine wall, it is necessary to conduct a complex of therapeutic and diagnostic measures for the prevention of pregnancy loss, especially in women with an obstetric anamnesis complicated by pregnancy loss.

The data obtained on the relationship between the site of embryo implantation and serum levels of progesterone, estradiol, testosterone, and prolactin are of diagnostic significance and may serve as an important prognostic criterion for pregnancy continuation.

Implementation of the work in practice. The results of the research have been implemented in the work of Women's Clinic No. 10, as well as in the work of the gynecological and pathological anatomy departments of SPb GUZ MSC 18.

The main provisions, materials, and conclusions are used in the educational process at the Department of Obstetrics, Gynecology and Perinatology of SPbGMA named after I.I. Mechnikov.

Validation of the work. The main provisions of the dissertation were reported at the Report Scientific-Practical Conference of SPbGMA named after I.I. Mechnikov (2006). Based on the dissertation materials, 7 scientific works have been published.

The main provisions of the dissertation to be defended:

1. The leading factors influencing pregnancy continuation in the first trimester are: the site of embryo implantation in the uterus, proliferative potential, the degree of morphofunctional differentiation and programmed cell death (apoptosis) of decidualizing endometrium cells, hormonal status, as well as the absence of an infectious agent.

2. A high level of proliferative activity and cellular differentiation, as well as a low level of programmed cell death of decidualizing endometrium cells upon embryo implantation into the mucous membrane of the posterior uterine wall, determine the formation of a full-term uteroplacental circulation.

3. The main pathogenetic factor of pregnancy loss upon embryo localization in the mucous membrane of the anterior uterine wall is the decrease in proliferative activity and differentiation of decidualizing endometrium cells.

4. The morphofunctional insufficiency of decidual base cells of the uterine mucous membrane is based on hormonal disturbances leading to a decrease in proliferative activity, cytodifferentiation, and an increase in the apoptosis index of decidualizing endometrium cells. The determining role in these processes belongs to the hormones estradiol, progesterone, and prolactin.

The dissertation consists of an introduction, 5 chapters, a conclusion, conclusions, practical recommendations, and a bibliography comprising 158 domestic and 171 foreign authors' works.