Estrogen and endometrial carcinoma.

1. It has become evident that the estrogen secreting tumors of the ovary are associated with endometrial carcinoma, but this association is most easily observed in the postmenopausal patient where the incidence of carcinoma has been reported at 10.3% (1. 02) to 24% (83). 2. The most consistent association of endometrial carcinoma is with polycystic ovarian disease, where 19 (34), 21 (152), and 25% (150) of young women with endometrial carcinoma had Stein-Leventhal syndrome (67). 3. A very significant discovery became known in 1967 when the peripheral aromatization of delta4 androstenedione to estrone was reported by Kase (94) and MacDonald (111,112). Since that time we have learned that endometrial carcinoma patients have an increased peripheral conversion (139) (0.1% compared to 0.027%), which is similar to that found in obese and aging patients, by Hemsell, et al (77). This can be 2 to 4 times greater than the young adult or the patient without cancer. Estrone produced peripherally in normal postmenopausal women can amount to 40-60 microng/day and rise as high as 120-180 microng/day in the endometrial neoplasia group (39). Similarly patients with polycystic ovary disease, hyperthecosis and lipoid cell tumors of the ovary demonstrate androgen excess with extraglandular conversion to estrone (2). 4. It has become apparent that the principal estrogen in the postmenopausal patient is estrone and that the estrone-estradiol ratio in the serum is higher in postmenopausal women with corpus cancer than similar patients without cancer (135). Clearly, we must find the effect of this estrone excess at the nuclear "acceptor" level; and does this imbalance create a hormonal environment conducive to the development of endometrial carcinoma when age (an extremely important factor) and an oncogenic agent are added? 5. With the lack of ovarian estrogen there is a relative excess of adrenal testosterone, dihydrotestosterone and delta4 androstenedione, the available precursors of extraglandular estrone (1). 6. With the passage of time it appears that endometrial carcinoma is associated with hypothalamic "hyperactivity" (31) which exhibits immunologic-biologic dissociation of LH as previously observed in persistent trophoblastic disease when measuring hCG. The significance of this is still unknown. In a like fashion a significant number of the at risk polycystic ovary disease patients have an increased LH secretion. 7. Patient susceptibility is required as seen in animal experiments where prolonged administration of stilbestrol is used and still only rabbits and mice developed a malignant change. 8. Long term exogenous estrogen appears to have caused malignant changes in the endometrium, but it was universally given over a prolonged period (4 or more years). The recent retrospective studies demonstrate an association of oral estrogen therapy with endometrial cancer, but prospective studies investigating dose and duration of all estrogen preparations need to be undertaken. 9...