Endometrial and Uterine Cancers

The uterus consists of smooth muscle (the myometrium) overlaid by an endothelial gland-studded mucosal stroma that makes up the endometrial lining of the uterine cavity. The endometrial lining undergoes cyclic response to hormonal stimulation during monthly menstrual cycles and throughout pregnancy. Cyclic proliferation and shedding is stimulated indirectly by the pituitary gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) and directly by the ovarian estrogens and progestins.

The endometrial lining begins each menstrual cycle as a thin stromal layer. As estrogen secretion increases, stromal and endometrial cells proliferate rapidly and the stromal layer thickens markedly. At ovulation, progestins augment estrogen secretions, causing the endometrial glands to accumulate glycogen and lipids in their cytoplasm. This “uterine milk” will provide a nutrient supply to the implanted ovum. If fertilization does not occur, both estrogen and progestin secretion declines, causing rapid involution of the endometrium and vasospasm in the uterine blood vessels. The endothelial lining, deprived of both blood nutriture and hormonal signaling, becomes hemorrhagic, undergoes necrosis, gradually separates from the uterus, and is expelled.

Subtle abnormalities in hormonal signals can interrupt the normal endometrial cycling, causing pain and bleeding. Anovulatory cycles result from excessive estrogen stimulation of the endometrium with absent or inadequate progestin influence. This pattern of hormonal imbalance can result from metabolic abnormalities such as marked obesity and malnutrition. Because they reflect hormonal imbalance, anovulatory cycles are also common at menarche and in the perimenopausal period and are not associated with endometrial cancer risk.

In contrast, endometrial hyperplasia, also called endometrial intraepithelial neoplasia, is strongly implicated as a precancerous lesion. Endometrial hyperplasia differs from benign anovulation in that the endometrium has a higher ratio of glands to stroma and glands exhibit crowding, enlargement, and shape irregularity. Two types of endometrial cancer have been characterized. Type I tumors represent up to 80 percent of cases and are associated with endometrial hyperplasia together with mutations in the ras protooncogene and the PTEN tumor suppressor gene. Decreased activity of the mutant PTEN gene increases sensitivity of endometrial cells to estrogen stimulation. Less common type 2 tumors develop in a background of atrophic endometrial tissue in older women and often have mutations in the p53 tumor suppressor gene. Some epidemiological studies suggest that obesity and lifestyle factors modify risk for [Page 226]type I endometrial cancer to a greater extent than for type 2 cancers.

The incidence of endometrial cancer is up to 10 fold higher in industrialized than rural countries and increases as populations migrate from less to more developed areas. Strong environmental influences have been identified, including estrogenic environmental pollutants, reduced parity, sedentary life style, use of exogenous estrogens for oral contraception or postmenopausal replacement therapy and increased body mass index (BMI). Unopposed estrogen it thought to be the link between risk factors and endometrial cancer. Mitogenic effects of estrogens, when insufficiently counterbalanced by progesterone can result in growth promotion and hyperproliferation in hormone dependent tissues.

Obesity is associated with increased total and bioavailable plasma sex steroid levels in both pre- and postmenopausal women. In postmenopausal women, estrogens are derived almost entirely by extraglandular aromatization of androgens in adipose tissue. Hyperinsulinemia, also associated with obesity, inhibits the hepatic synthesis of sex-hormone-binding globulin (SHBG) and can enhance the synthesis of androgens by the gonads and adrenal glands.

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