1.1. ANATOMY AND FUNCTION OF THE UTERUS
The uterus is a female reproductive sex organ. It is a hollow, thick-walled, muscular organ with the shape of an inverted pear. It is located in the pelvic cavity above the vagina, above and behind the bladder and in front of the rectum (Figure 1). Although the shape and position of the uterus changes dramatically during pregnancy, in its non-pregnant state, it measures on average 8 cm long, 5 cm wide and 2.5 cm in diameter 1. The uterus has three major regions: the fundus, the curved upper area where the Fallopian tubes connect to the uterus – it is the wider part of the organ, of around 5 cm; the body, the enlarged main part which lies below the fundus and is separated from the cervix by a slight constriction, the isthmus; and the cervix, the inferior cylindrical narrow part of 2-3 cm length that opens into the vagina (Figure 1).
Figure 1. Location and anatomical parts of the uterus.
The wall of the uterus is thick and has 3 layers 2 (Figure 1):
• The perimetrium, the outer serosal layer of the uterus that consists of a thin visceral peritoneum.
• The myometrium, the thicker middle layer (1-2 cm thick) of the uterus composed primarily of smooth muscle cells in a framework of arterial and venous blood supply supported by an underlying connective tissue. It allows the uterus to expand during pregnancy and to contract during childbirth.
• The endometrium, the inner hormone-responsive mucosal lining of the uterus.
The functional uterus is an essential organ for reproduction. At ovulation, the wall of an ovarian follicle ruptures, releasing a secondary oocyte that passes into the uterine cavity through the Fallopian tubes. If fertilization occurs, the blastocyst implants on the endometrial
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lining. As the embryo develops into a fetus, it triggers changes within the endometrium that lead to the formation of the placenta. The placenta acts to provide oxygen and nutrients to the fetus, whilst removing carbon dioxide and other waste products 3. At the end of pregnancy, the uterus plays a critical role in the process of childbirth. It dilates the cervix and contracts the myometrium at term to deliver the fetus, through the vagina, out of the mother´s body 4.
1.2. HISTOLOGY OF THE ENDOMETRIUM
The endometrium consists of three main constitutive elements: i) a simple columnar epithelium of ciliated and secretory cells in the surface; ii) an underlying matrix of cellular connective tissue stroma containing a rich supply of blood vessels; and iii) simple tubular uterine glands formed by invagination of the epithelium that extend through the entire thickness of the stroma (Figure 2). Those epithelial and stromal cells coexist with other minor subtypes of cells, such as lymphocytes and other leucocytes, among others 2. Around 90% of endometrial carcinomas originate from the epithelial glands in the endometrium.
1.3. PHASES OF THE ENDOMETRIUM
1.3.1. Functional endometrium
The functional endometrium has a lifetime equal to the reproductive life of an adult, i.e., from the menarche to the menopause. The main characteristic of the endometrium is its perfect response to the hormone stimuli from the ovaries 1. This response produces important morphologic changes in all the elements of the endometrium during the endometrial cycle, in order to prepare itself for receiving a fertilized oocyte 5. If the fertilization does not occur, the functional layer of the endometrium is shed and expulsed, leading to menstruation, which occurs approximately every 28 days.
Functionally, the endometrium can be divided into two layers based on their involvement in the changes of the menstrual cycle 2.
• The functional layer is the luminal part of the endometrium. It is the part that suffers the cyclic changes, it is shed at the time of menstruation and built up again under the stimulation of ovarian steroid hormones.
• The basal layer is located below the functional layer, adjacent to the myometrium.
It is highly vascular, it changes little during the menstrual cycle and is not shed during the menstruation. It serves to regenerate the functional layer after each menstruation.
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Figure 2. Endometrial cycle and endometrial histology. E, simple columnar epithelium; S, stroma;
G, uterine glands.
The functional endometrium goes through four different stages, related to the three phases of the endometrial cycle (proliferative, secretory, and menstrual) and to pregnancy. All of them have different histological and molecular features (Figure 2).
1.3.1.1. Proliferative endometrium
The proliferative endometrium is present during the phase prior to the ovulation period, between days 4 and 14 1.
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Immediately after the menstruation, the thickness of the endometrium is 1-2 mm. The proliferative endometrial tissue is characterized by its great capacity to proliferate and increase its thickness as a result of estrogen stimulation.
The proliferative endometrium is composed of rectilinear endometrial glands, which are delimited by pseudo-stratified nuclear cells and mitotic components. There is a prominent mitotic activity in both the glands and the stroma. The stroma is dense with cells showing a reduced cytoplasmic fraction 6,7.
During these days, the hypothalamus releases gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates the maturation of a follicle within an ovary.
Ovulation occurs on day 14 and it is associated with a high release of estrogen and an LH surge.
1.3.1.2. Secretory endometrium
The secretory endometrium is present just after the ovulation period, between days 15 and 28. From day 20 to 24 of the cycle, the "window for implantation" occurs, which is the period of time when endometrial receptivity for blastocyst implantation is at its highest 1.
Changes in the endometrium during this phase are oriented to prepare a nutritive soil for the blastocyst implantation and are supported by the appearance of progesterone.
This endometrial tissue is characterized by tortuous endometrial glands that continue growing and by the predecidual transformation of stromal cells, which increase their cytoplasmic fraction and acquire a cubical morphology. A particular phenomenon of this phase is the appearance of subnuclear vacuoles containing glycogen and mucopolysaccharides. These vacuoles move to the luminal surface where they are secreted. The stroma becomes edematous and spiral arteries appear 6,7. The endometrium in this phase can increase its thickness up to 8 mm.
1.3.1.3. Menstrual endometrium
This menstrual endometrium is present during the menstrual phase, between days 1 and 4 of the endometrial cycle 1, and it is formed if the oocyst is not fertilized.
In the absence of conception, chorionic gonadotrophin (hCG) is not produced. In a first phase, the levels of progesterone decrease and a structural detachment of the functional layer of the endometrium occurs along with increased leucocyte infiltration, hemorrhage and necrosis. In a second phase, and as a consequence of the hormonal stimuli, the endometrium begins its regeneration from the basal layer which was not dissociated.
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1.3.1.4. Endometrium at pregnancy
This endometrial tissue is only formed if the oocyst has been fertilized and the blastocyst has implanted and begun to proliferate within the endometrium. In this case, the endometrium increases its hypertrophy and secretions. Endometrial glands are rich in glycogen and stromal cells decidualize, becoming bigger, polygonal, with a high fraction of cytoplasm 1.
1.3.2. Atrophic endometrium
The non-cycling endometrium becomes gradually atrophic after the menopause. Nowadays, almost a third of the life of a woman is postmenopausal, and over 80% of endometrial carcinomas develop during this period 8.
In this phase, the endometrium suffers important histological modifications and loses its ability to proliferate and secrete. The main reason for these modifications is the privation of estrogen and progesterone. The atrophic endometrium is thin (1 to 3 mm thick), with loss of distinction between the basal layer and the functional layer. Histologically, it maintains the three main constitutive elements but with significant alterations: i) small tubular glands may initially retain some proliferative activity, although weak; however, with further decline of estrogen secretion they become functionally inactive; ii) glands are widely spaced, lined by cuboidal epithelium showing neither secretory nor proliferative activity; iii) the stroma is dense and fibrous. With complete absence of ovarian function, the endometrium falls into cystic atrophy, ending up as a thin layer full of cystically dilated endometrial glands lined by a flattened inactive epithelium 8,9.
However, estrogen stimulation may continue to some extent, since androgens, which are secreted by the menopausal ovaries and adrenal cortices, can be converted into estrogens.
In fact, the majority of non-cycling endometria are thin and atrophic, but only half of the cases are inactive 10. The remaining show a weak proliferative activity, indicative of an endometrium that responds to continuous low levels of estrogens unopposed by progesterone. Under the influence of prolonged levels of estrogens, the postmenopausal endometrium may turn into the so-called disordered proliferative endometrium 6, or give rise to atypical endometrial hyperplasia or endometrial intraepithelial carcinoma 11,12 , from which an endometrial carcinoma can develop.
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