2.4. Endometrial function
2.4.1. Uterine development
The Müllerian duct, the antecedent of the uterus, arises from coelomic mesothelium in close association with the Wolffian duct. The uterus develops as a muscular expansion of the Müllerian duct together with the fallopian tubules and the upper portion of the vagina, which are also Müllerian derivatives (Healy & Hodgen 1983). As stated earlier, the formation of the Müllerian duct is dependent on Wnt-4 action, and in Wnt-4 knockout mice the Müllerian duct is absent (Vainio et al. 1999).
The uterus can be divided into three major functional elements. The first one is the endometrium, a glandular membrane that lines the uterine cavity. Its main purpose is the implantation and nourishment of the early embryo. The second component, the myometrium is the smooth muscle body of the uterus located under the endometrium. The third component, the cervix, opens to the vagina and contains glands that supply mucus to the vagina. The endometrium itself consists of three independent structural components the glands, stroma and blood vessels. In adult life, all three layers are under cyclical regulation of ovarian steroids.
2.4.2. Regulation of endometrial function during the menstrual cycle
The endometrium undergoes cyclic phases of proliferation. To assure optimal conditions for implantation the endometrium is swiftly discarded and regenerated if fertilization does not occur (Lockwood et al. 1997) (Fig. 11).
Regeneration of the endometrium ensues immediately after menstruation. Significant stromal proliferation is observed throughout the follicular phase, which persists until ovulation. Follicular phase proliferation is characterised by upregulation of estrogen and progesterone receptors in glandular epithelium and in the stroma. Apoptosis has been morphologically (Hopwood & Levison 1976) and biochemically (Tao et al. 1997) detected in human endometrium. Expression of the regulating factors Bcl-2 and Bax, has also been observed (Otsuki et al. 1994, Koh et al. 1995, Tao et al. 1997, Tao et al. 1998). Animal studies indicate the participation of ovarian steroids in the control of endometrial apoptosis, since removal of steroid action leads to increased endometrial cell death (Pecci et al. 1997).
2.4.3. Endometrial cancer and hyperplasia
Endometrial carcinoma is one of the most frequently found carcinomas of the female reproductive system (Purdie & Green 2001). It has been proposed that the path to development of endometrial carcinoma goes through pre-malignant stages of endometrial hyperplasia (Czernobilsky & Lifschitz-Mercer 1997). Endometrial hyperplasia is thought to arise from an unopposed estrogen influence that drives endometrial cell proliferation, while an alternative pathway, utilising improper function of the tumour suppressor p53, has also been suggested (Kounelis et al. 2000). Endometrial hyperplasias are divided into four subcategories: 1) Simplex type hyperplasia that includes cystic glandular hyperplasia, 2) simplex type hyperplasia with cellular atypia (this subtype is exceptionally infrequent), 3) complex type hyperplasia without atypia, and 4) complex type hyperplasia with atypia. Hyperplasias without cellular atypia very seldom develop into cancer, i.e. in less than 2% of cases, while complex hyperplasia with atypia leads to cancer diagnosis in 23% of the patients (WHO 1994, Kurman & Norris 1982).
According to World Health Organization, endometrial carcinomas can be divided into three grades. Grade I carcinoma consists of well differentiated carcinoma, grade II represents moderately differentiated disease and grade III carcinoma comprises poorly differentiated cancer (WHO 1994).