Manggiasih Dwiayu Larasati, et. all | Characteristics of Endometrial Cells......

Journal Educational of Nursing (JEN) Article history: Vol. 4 No. 1 – January – June 2021; page 9-19 Received: February 19, 21 p-ISSN : 2655-2418; e-ISSN : 2655-7630 Revised: February 25, 21 journal homepage: https://ejournal.akperrspadjakarta.ac.id Accepted: March 02, 21 DOI : 10.37430/jen.v4i1.82

Characteristics of Endometrial Cells and the Factors that Influence the Implantation Process

Manggiasih Dwiayu Larasati1, Ita2 Department of Midwifery, RSPAD Gatot Soebroto College of Health Sciences, Jakarta-Indonesia Department of Nursing, RSPAD Gatot Soebroto College of Health Sciences, Jakarta-Indonesia E-mail: [email protected], [email protected]

Abstract Infertility is a global health problem faced by 8 - 10% of couples in the world. It means 50 - 80 million couples have infertility problem. Knowledge about comprehensive and profound reproductive system is main asset for managing infertility. When look at various factors those contribute to women infertility, so the role of is very important. The optimal endometrial environment for receiving blastocyst is a major factor in the process of implantation and pregnancy. This study attempts to review and compare sources from research article, case report, and reviews from reputable international journals. Research by Germeyer et all (2010) shows that optimal growth and development of endometrium are factors those greatly contributes for successful implantation which is continued to pregnancy. The same thing is revealed by Neykova review (2020) which states the success implantation process is determined by the quality of the , the readiness of the endometrium to accept the result of conception and interaction, and communication of molecular cells. Currently, various studies are being developed for evaluating endometrium condition through genetic improvement, the use of new biomarkers, non-invasive method even sophisticated method such as proteomic technique Endometrial Receptivity Assay (ERA) in order to solve women infertility problem.

Keyword: Endometrium, Infertility, Implantation, Pregnancy.

Introduction Secondary infertility is when a married Infertility is a source of complaints and couple who had previously had children anxiety for married couples. Infertility cannot have children again for two years affects about 50 - 80 million couples in the even though the couple is not using world [1]. In Indonesia there are contraceptives and is not breastfeeding [3]. approximately 12% of infertile couples [2]. The cause of infertility can come from Infertility is defined as the inability of a the husband or wife, or both. According to married couple to become pregnant for a statistics, 40% of infertility occurs in the period of six months to one year without female reproductive system, 40% occurs in using contraceptives and having active the male reproductive system, and 20% has intercourse [1]. no known cause [3]. Infertility in the female WHO Scientific Group classifies reproductive system can be caused by infertility into two types, namely primary several things, including menstrual infertility if a husband and wife have not abnormalities, abnormalities in the fallopian had children for two years even though the tubes, , and endometrial lining of the couple does not use contraceptives. [1].

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Various methods have been used to biomarkers, non-invasive methods and overcome the problem of infertility, one of even sophisticated methods such as the which is an engineering technique called in Endometrial Receptivity Assay (ERA) vitro fertilization (FIV). Fertilization proteomic technique in order to overcome technique which was performed in the infertility problems in women [6]. laboratory was successfully performed for Due to the close relationship between the first time in 1978. This success gave endometrial disorders and infertility, new hope to couples who have difficulty therefore, it is important to carry out in- having children [1]. However, in vitro depth studies and discussions about the fertilization techniques cannot guarantee nature or characteristics of endometrial 100% success for a couple to have cells and what factors influence their offspring. The success rate for this development during the implantation technique averages only about 35%. The process. failure of in vitro fertilization techniques is thought to be caused by failure of follicle Method formation, too low estradiol levels, and less This article is a literature review than ideal endometrial conditions [2]. compiled by discussing a number of The endometrium is an organ that plays research articles, case reports, review an important role in the process of articles obtained from reputable implantation and pregnancy. Research by international journals. There are around 389 Germeyer et all in 2010 showed that articles from a number of reputable journals impaired endometrial growth, such as a such as Elsevier, Lancet, Sciencedirect and decrease in the rate of proliferation, is a number of other publishers. Based on the one of the causes of failure in implantation inclusion criteria, 20 articles were reviewed and pregnancy [4]. In addition, several in this review. studies have shown that one of the causes of the low pregnancy rate in humans is an Result and Discussion overly thin endometrial lining [5]. The 1.Endometrium same thing was expressed by Neykova et al The endometrium is a thin layer found in 2020 which stated that the success of the in the inferior part of the uterus which is implantation process was determined by rich in tortuous blood vessels. The most the quality of the embryo, the readiness of important physiological function of the the endometrium to accept the results of endometrium is in the process of conception and molecular interactions and implantation as a result of fertilization. The communication between cells [6]. endometrium is important in the menstrual Based on the results of the study, cycle as a reproductive period. Most of the Cohen et all stated that patients with In endometrium is released during Vitro Fertilization who experienced menstruation, which then grows again in repeated implantation failure need to the proliferation phase followed by the consider endometrial histology during the sectoral phase [8]. Figure 1 shows these secretion phase [7]. In fact, various studies structural and functional changes in order are currently being developed to evaluate to prepare for blastocyst implantation and the condition of the endometrium through to support embryonic growth in early genetic improvement, the use of new pregnancy [6].

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Figure 1. Implantation Process and Decidua Formation.

The implantation process consists of surrounding the embryo turn into decidual apposition, adhesion or attachment, (D) cells. Immune cells such as invasion or penetration and decidualization macrophages and Uterine Natural Killer or formation of decidua. During apposition (uNK) cells play an important role during (A), blastocyst will express L-selectin the decidualization process, namely to while expression of Mucin-1 (MUC-1) form an environment conducive to will block blastocyst and prevent it from successful implantation. implanting. Furthermore, L-selectin will (http://smart.servier.com) [9] interact with its ligands which are The endometrium is composed of expressed mainly on pinopod during the stromal cells surrounded by a columnar implantation process. Early in the adhesion epithelial layer with glandular cells phase (B), the blastocyst initiates cleavage extending towards the stroma [10] (Figure of MUC-1 at the implantation site to 2). The lining of the endometrium can be ensure successful implantation. Cytokines, divided histologically and functionally such as Leukemia Inhibitory Factor (LIF), into three. The innermost or basal layer play an important role during the (stratum basale) is attached to the implantation process by supporting the myometrium. The middle layer is interaction between and characterized by a spongy-looking stroma endometrial cells. During the invasion or called the stratum spongiosum. The penetration phase (C), trophoblast cells superficial layer is composed of a compact from the blastocyst penetrate the looking stroma called the stratum endometrial into the stroma. compactum. The middle layer is thicker Extra villiary trophoblast cells begin to than the superficial layer. The middle and multiply and differentiate into inner superficial layers are grouped into cytotrophoblasts and outer functional layers, because both layers syncytiotrophoblasts. After implantation show marked histological changes begins and the embryo penetrates the throughout the reproductive cycle [11]. luminal epithelium, the stromal cells

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Figure 2. Histological cross section of the endometrium [12] The lining of the endometrium is a layer (LH-surge) in the middle of the cycle that is responsive to changes in reproductive resulting in ovulation. The increased LH will hormones, so changes in this layer vary persist for about 24 hours and decrease in the throughout the reproductive cycle and can be . Within a few hours after the LH used as an indicator of current hormonal increases, the amount of decreases fluctuations. The constituent layer on the [2]. endometrial wall of the uterus is a layer of The luteal phase is characterized by columnar epithelium and lamina propia enlargement of the granulosa cells to form a which consists of connective tissue and and accumulate yellow pigment glands [10] [11]. (lutein) and the follicle will become the 2. Endometrial Changes During the corpus luteum. Vascularization in the granulosa layer also increases and reaches a Menstruation is a uterine cycle peak on days 8-9 after ovulation. The characterized by the bleeding process. granulosa cells in the corpus luteum produce Menstrual cycle length is the distance large amounts of the hormone , between the previous cycle and the new while theca cells produce the hormone cycle. The normal menstrual cycle length is estrogen, so the two hormones will increase 28 days but variations are wide enough for in the luteal phase. Starting 10 - 12 days after each individual. The normal menstrual cycle ovulation the corpus luteum undergoes (ovarian cycle) is divided into follicular gradual regression accompanied by a phase and luteal phase [2]. decrease in capillary capillaries followed by The follicular phase is aimed at a decrease in the secretion of progesterone developing follicles in the ovaries due to the and estrogen. The endometrium undergoes influence of the increased FSH. The increase four phases in the menstrual cycle (Figure 3), in FSH is caused by regression of the corpus namely: luteum, so that steroid hormones are reduced. a. Menstrual or menstrual phase. During The growing follicles cause the production of this time the endometrium is released estrogen to increase, it suppresses the from the uterine wall accompanied by production of FSH. bleeding. Only a thin layer remains, The production of LH at this time is also called the stratum basale, this stage lasts increasing, but its role is only to help make for about 5 days. The decrease in estrogen in the follicles. Follicular progesterone and estrogen hormones development ends when the plasma estrogen will stimulate prostaglandins which will levels rise. This provides positive feedback cause the spiral arteries in the to the cyclic center and a sudden peak release endometrial functional stratum to

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experience vasoconstriction resulting in b. The pre-ovulatory phase or the disruption of blood flow to the proliferation phase is the time between functional stratum resulting in the end of menstruation and ovulation. temporary ischemia and ultimately The pre-ovulation phase has a long cycle leading to cell necrosis in blood vessels and varies in each phase, which is about in the functional stratum. After 6-13 days for a 28 day cycle. Estrogen vasoconstriction occurs, the spiral will be released into the blood by the arteries will return to vasodilation, growing ovarian follicles to stimulate which will result in the shedding of the endometrial repair in the uterus. The necrotic functional stratum from the cells of the basal stratum undergo remaining part of the endometrium. The mitosis and produce a new functional endometrium becomes around 2-5 mm stratum which causes the endometrium because only the basal stratum is to thicken. The thickness of the permanent. Menstrual blood flows out endometrium is doubled to about 4-10 through the uterus, cervix and vagina mm [12]. [12].

Figure 3. Changes in hormonal regulation in the uterus and ovaries [12] c. Ovulation phase. This phase occurs Gonadotropin Releasing Hormone when the rupture of the de graff (GnRH) and Luteinizing Hormone follicle occurs and the secondary (LH) which causes the ovulation phase oocyte from the to the uterus as follows: passes through the uterus. The 1) GnRH release from the ovulation phase occurs on day 14 of hypothalamus is caused by the 28 day menstrual cycle. The stimulation of high estrogen secondary oocyte remains surrounded concentrations. Gonadotropins in by the zona pellucida and corona the anterior pituitary directly radiata during the ovulation phase stimulate LH secretion. [12]. The high estrogen hormone in the 2) The release of FSH and LH from pre-ovulation phase provides positive the anterior pituitary is assisted by feedback to cells that secrete GnRH.

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3) LH causes the rupture of the de requires coordination and communication graff follicle and releases the in autocrine, paracrine, and endocrine ways secondary oocyte about 9 hours [15]. after the peak of LH. The secondary Implantation in humans consists of ovulation remains surrounded by three stages, namely apposition, adhesion, the zona pellucida and corona and invasion. The first step in the radiata which will go to the uterus implantation process is apposition, which through the fallopian tube [12]. is the initiation of communication between d. Post ovulation phase or secretion the blastocyst and endometrial receptivity stage. This phase begins after which is influenced by hormones, ovulation and lasts from day 14 to 28. cytokines, and growth factors. At the time Progesterone and estrogen will be of apposition there is adhesion of the produced by lutein cells from the blastocyst to the part of the endometrium corpus luteum which will help the called the pinopod. Pinopod is a functional growth of the endometrium gland, marker of endometrial receptivity. endometrial thickening of about 12-18 The next step is adhesion, namely mm and increase in endometrial increased physical interaction between vascularization. The secretory activity blastocytes and the endometrium. The last of the endometrium starts to secrete stage is the invasion process, namely the glycogen and this period is called the penetration of the embryo into the secretion phase. The decrease in the epithelial layer and the stroma to form hormones progesterone and estrogen vascularization with the mother's uterus [6] occurs due to degeneration of the [15]. corpus luteum due to no fertilization. The process of implantation of The decrease in these two hormones trophoblasts in the endometrium is causes menstruation in the next cycle influenced by several factors that play an [12]. In this phase the endometrium important role among cytokines and remains approximately still thick, but growth factors. The following will briefly the shape of the gland changes to a describe the role and mechanism of each long, twisting and secretion that factor on endometrial growth during the becomes increasingly visible and implantation process. obvious. The endometrium has 3.1 Hormonal Roles accumulated glycogen and lime which Ovarian steroid hormones, namely will be needed as food for a fertilized estrogen and progesterone, play an egg. The purpose of these changes is to important role in the embryo implantation prepare the endometrium to accept the process. During the implantation process incoming sperm and the egg to be the endometrium undergoes transitions and ready for fertilization [13] [14]. changes morphologically and functionally 3. Implantation and its Influencing under the influence of ovarian hormones. Factors Progesterone and estrogen are the main Implantation is a dynamic process that hormones that affect endometrial growth involves the embryo, starting from [2] [15]. hatching, apposition, adhesion, and invasion of the endometrial epithelium. The success of the implantation process depends on the quality of the blastocytes, the receptiveness of the endometrium, and the communication or synchronization between the embryo and the endometrial lining itself. The implantation process

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which has bind to RE α on stromal cells triggers the emergence of epidermal growth factor (EGF) or what is called paracrine factor. These paracrine factors then stimulate the mitotic process in epithelial cells [17]. The action of EGF in inducing the proliferation of epithelial cells is as follows. Paracrine factor (EGF) produced by endometrial stromal cells will bind to its receptors (EGFR) found on the endometrial epithelial cell membrane. This binding event causes the transcription factor to be activated and the transcription and translation processes occur to form Figure 4 The effect of the hormones estrogen specific proteins. Specific proteins that and progesterone on endometrial cell changes have been formed will induce mitotic (proliferation and secretion phase) [16] events or cell proliferation so that the Figure 4 shows that the hormone endometrial epithelial cells thicken [17]. estrogen plays an important role in the Progesterone, a hormone produced by growth, development, and secretory the ovaries, plays an important role in the activity of endometrial cells [16]. The preparation of the endometrium for estrogen hormone that has been formed implantation of the product of conception. will be transported through the blood to its Progesterone also maintains the viability of target cells, including endometrial cells. the embryo at the pre-implantation stage. The hormone then binds to the α estrogen Various cellular interactions lead to receptor (RE α) to form a hormone synchronization between embryonic complex with RE α. The hormone complex development and endometrial preparation. with receptors will regulate target gene In the synchronization process, the role of expression by binding to estrogen response steroid hormones is needed. Continued elements (EREs). This binding event progesterone production from the corpus causes a specific mRNA transcription and luteum stimulates the differentiation and protein translation process. The specific proliferation of endometrial stromal cells protein formed will induce the proliferation [18]. of stromal and epithelial cells as well as thickening of the endometrial lining [16] [17]. The process of proliferation of endometrial cells occurs either directly or indirectly. Endometrial stromal cells have enough RE α, so that these cells can proliferate directly. However, this does not occur in endometrial epithelial cells. Endometrial epithelial cells have a little RE α so that the process of mitosis in these Figure 5. The mechanism of action of the cells must be assisted by paracrine factors hormone estrogen on endometrial cells [17] produced by endometrial stromal cells. Endometrial epithelial cell proliferation is The hormones estrogen and induced by the process of stromal cell progesterone are known to also regulate proliferation. Figure 5 shows that estrogen HOXA 10 expression and pinopod

Journal Educational of Nursing (JEN) Vol. 4 No. 1 (2021) 15 Manggiasih Dwiayu Larasati, et. all | Characteristics of Endometrial Cells...... formation (Figure 6). HOXA 10 is known The endometrium produces cytokines to be a gene that is produced by the that play a role in the implantation process, female reproductive tract, the number namely colony stimulating factor1 (CSF- increases at the time of the implantation 1), leukemia inhibitory factor (LIF), and window. Several studies have shown that interleukin-1 (IL-1). Expression of CSF-1 this gene is closely related to pinopod and receptors for CSF-1 was found in both formation and endometrial receptivity. the endometrium and the preimplantation Good pinopod development is related to embryo. Leukemia inhibitory factor (LIF) one's fertility [19]. is one of the cytokines of the interleukin 6 Several studies have shown that the group (IL6) which is essential for chorionic gonadotropin hormone from the successful implantation, is expressed in embryo is regulated by paracrine factors embryos and adult tissues, and is secreted under the influence of progesterone. The by the uterus in high enough levels [15] chorionic gonadotropin hormone [21]. Expression of IL6 is found in furthermore regulates endometrial endometrial glandular epithelial cells differentiation for blastocyst implantation during the secretory phase [15]. and increases the synthesis of Β-receptor LIF On the surface of the progesterone in the ovaries. In addition, cell binds to glycoprotein gp-130, a form the hormone progesterone is also known of high affinity receptor that stimulates to suppress immunosuppressive effects signal formation and induces molecules and plays a role in protecting the fetus and contributes to stromal cell expression. from the immune system. Progesterone LIF plays a role in the endometrial stimulates NK cells to change the function function of humans and domestic species. of NK cells to become more tolerant of Furthermore, it has been suggested that the embryo [18]. LIF mRNA and protein are expressed in Apart from estrogen and progesterone, glands in the endometrium during the prostaglandins (PGs) also have an luteal phase of the menstrual cycle when important role in reproductive processes implantation is about to occur [21]. such as ovulation, implantation, and LIF-rβ and gp-130 expressed menstruation. The biosynthesis of these throughout the lumen of the endothelium prostaglandins is regulated by the enzyme (LE) in women proved fertile. The soluble cyclooxygenase (COX-1 and COX-2). form of gp-130 is excreted by the Several studies have shown that women endometrium, is formed by proteolytic who have failed implantation have low fractions and excreted in high levels in the levels of the enzyme COX-2 [20]. middle of the luteal phase. This situation is stimulated by estrogen with progesterone in the culture of endometrial epithelial cells. This suggests that a high likelihood of low levels of potential antagonists regulating activation of the membrane- bound IL-6 family receptors [21]. The misregulation of soluble gp-130 in unexplained infertility patients is additional evidence of the role of the cytokine IL-6 family in normal pregnancy endometrial function. In addition, a correlation has been shown between LIF and LIF-R levels and Figure 6. Mechanism of the hormones estrogen LE formation in the uterine cavity, and progesterone on pinopod formation [17] primarily as a sign of receptivity. Several 3.2 Role of Cytokines studies have shown that LIF expression in

Journal Educational of Nursing (JEN) Vol. 4 No. 1 (2021) 16 Manggiasih Dwiayu Larasati, et. all | Characteristics of Endometrial Cells...... several studies is associated with recurrent estradiol will bind to its receptors and miscarriage and some conditions of cause uterine receptivity [21]. unexplained infertility according to their This will stimulate the uterus to role in early pregnancy. Expression of LIF produce growth factors such as epidermal is absolutely necessary in the implantation growth factors (EGF), heparin-binding process, without LIF implantation will not EGF (HB-EGF) and transforming growth occur [21]. factor (TGF) [15]. These proteins will 3.3. The Role of Growth Factor cause the expression of the In transfer embryos, the highest cyclooxigenase enzymes (COX enzyme), implantation rate is obtained when the which is the main enzyme that synthesizes reproductive cycle of the donor embryo is prostaglandins. The COX-2 enzyme is in sync with the recipient cycle. important in the implantation process Synchronization of the uterine because in mouse experiments if a COX-2 endometrium and blastocysts can be enzyme defect is found, the endometrium achieved through the influence of the cannot accept the embryo so that ovarian hormones progesterone and prostaglandins are very important in estrogen. Progesterone will stimulate a supporting the ability of the uterus to preseptive stage that is responsive to accept blastocysts even though the estrogen. In the uterus, estrogen or mechanism is not yet clear [21].

Figure 7. The role of hormones, growth factors, and cytokines in the implantation process [15]

Heparin-binding EGF is thought to required to maintain the uterus in an play a role in the implantation process embryo-receptive stage. If there is no IL- because it is only secreted by cells at a 1 receptor or IL-1 receptor is not potential site for implantation in mice, functioning, there will be no adhesion namely on the epithelial surface of the between the uterus and the trophoblast. It uterine cavity. In addition, HB-EGF is has been suggested that the process of able to stimulate trophoblast growth and adhesion and subsequent invasion of the blastocyst attachment sites. Trophoblasts endometrium involves adhesion for this growth factor and IL-1 are molecules [21].

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