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New Insights into Pathology of Endometrial Carcinoma Current Topics in Menopause 255 INCIDENCE AND AGE Endometrial carcinoma is the most common gynaecological malignancy in many parts of the world, including the United States, Australia and Europe [1-3]. The disease is ten times less common in Asia and Africa [4, 5], probably as a result of differing patterns in exposure to risk factors, such as obesity and obesity related factors, estrogen replacement therapy (ERT) (see below). It is a disease of aging: 82% of women having the tumor are postmenopausal [6-8] and, at this age group, the incidence trends are rising, not least because of prolonged life expectancy [7, 9]. The peak incidence of endometrial carcinoma is usually between 55 and 60 years. CLINICAL PRESENTATION Abnormal vaginal bleeding is the most common clinical manifestation of endometrial carcinoma, and 5 to 10% of all women presenting with postmenopausal bleeding might be expected to experience the condition [10, 11]. Pain appears only late in the course of the disease, while the occasional patient may be asymptomatic [12]. PATHOGENESIS/RISK FACTORS Clearly, there are many accounts on the aetiology and pathogenesis of endometrial carcinoma. Most, if not all, of them take Bokhman’s dogmatic view that endometrial neoplasms developing at menopause are non estrogen-induced [13], without giving a clue as to the possible factors which may be important. Despite our initial sympathy [14], we no more share this dualistic view of endometrial carcinogenesis but, on the basis of pertinent observations made over the years, we feel that endometrial carcinomas should no longer be regarded as “estrogen dependent” (Type I carcinomas occurring in premenopausal women) or “estrogen independent” (Type II carcinomas developing during menopause) [13, 15-18], but rather as neoplasms of high and low hormone dependency [6, 19, 20]. There is, indeed, growing evidence that endometrial carcinomas developing at menopause are, in essence, subject to similar risk factors as do those arising in young premenopausal women, and that in both cases the relevant factors operate through a single pathogenetic pathway, which is prolonged estrogenic stimulation of the endometrium, unopposed by progesterone action [6, 19, 21-23].
256 Current Topics in Menopause Sivridis and Giatromanolaki At first sight, this widening of the “unopposed estrogen” concept to include tumours of the postmenopausal age may seem intriguing, yet estrogens are produced not only by the ovarian follicles during the reproductive years, but they are also produced during the menopause from androgens secreted by the adrenal glands and the ovarian stroma [24-26]. This continuing production of estrogens after the decline of ovarian function, in parallel with the absence of antagonism by progesterone, most probably reflects the dramatic increase in the incidence of endometrial cancer during the menopause [27, 28]. Since the conversion of androgens to estrogens (estrone) is succeeded through peripheral aromatization in the adipode tissue, postmenopausal obesity, a prevailing feature at this age group, constitutes the main source of estrogens in postmenopausal women [22]. Other contributing, hormone-related, factors are described below. First, there is increased production of androgens in adrenal and ovarian tissues among postmenopausal women [27, 29] which is associated with 2.8-fold increased risk of developing endometrial carcinoma, after adjustment for other factors [21, 23, 30, 31]. More specifically, the adrenals secrete androstenedione, while the postmenopausal ovaries secrete mainly androstenedione and small amounts of testosterone [32]. It appears that an increased androgen production occurs postmenopausally in all patients with endometrial carcinoma [33] (see below), while a smaller proportion of “androgen drive” neoplasms are evoked by ovarian stromal hyperplasia and hyperthecosis [29, 34] or the less common conditions of granulosa and theca cell ovarian tumors which are all capable of producing estrogens [24, 35]. Second, there is increased conversion rate of androstenedione and testosterone to estrone in postmenopausal women, which is 3 to 5 times above normal [35, 36]. In fact, most circulating estrogen is biologically active estrone in this age group [37, 38], and high estrone levels were positively correlated with the development of endometrial adenocarcinomas [31]. The increased risk was calculated 3.8 times greater among postmenopausal women, although adjustment for other risk factors, particularly body mass index, diminished the effect to 2.2 [21]. The conversion occurs in the adipose tissues. Third, the effective (unbound) concentration of estradiol and estrone in the circulation is increased, whereas the serum levels of sex hormone-binding
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