Catherine S. Bradley MD, Ivor Benjamin, MD
University of Pennsylvania Cancer Center
Last Modified: November 1, 2001
Many women who have undergone bilateral oophorectomy (removal of the ovaries) as part of their treatment for endometrial cancer have significant morbidity related to estrogen deprivation. While vasomotor symptoms (hot flushes) and vaginal atrophy (shrinkage) leading to dyspareunia (painful sexual intercourse) are very common and may have a significant impact on a woman's quality of life, they are not life threatening. Osteoporosis (weakening of the bones) and an increased risk for development of atherosclerotic cardiovascular disease (hardening of the arteries) are all a consequence of loss of estrogen. Osteoporosis may contribute to the risk of hip fractures in elderly women that is associated with a mortality of up to 24% within one year of the fracture .
Adenocarcinoma of the endometrium is an estrogen-sensitive neoplasm. Estrogen replacement therapy (ERT) has traditionally been withheld from women after treatment for endometrial cancer, based on the belief that it might stimulate any residual tumor cells and increase the risk for recurrent disease. However, this theory has never been substantiated, and recent data suggest that ERT is safe in patients with a history of low-risk endometrial cancer.
Two retrospective studies have examined this issue. In 1986, Creasman et al.  studied 221 patients with Stage I endometrial cancer (limited to the uterus). A historical control group with a similar distribution of accepted prognostic factors (substage, tumor grade, depth of invasion, nodal metastasis, peritoneal cytology, and hormone receptor status) were compared with a study group receiving ERT. The estrogen-treated patients used both oral and vaginal therapy, and the length of ERT ranged from three to 84 months (median 26 months). The interval of time from cancer therapy to initiation of ERT ranged from zero to 81 months (median interval 15 months). Median follow-up times after initial therapy for cancer were 60 months in estrogen users and 42 months in nonestrogen users, and in the first group, the median follow-up time after ERT was initiated was 32 months. Among the 174 nontreated patients there were 26 recurrences (14.9%), and in the 47 patients taking ERT there was only one recurrence (2.1%). Thus, the estrogen-treated group did not have an increased risk of recurrence. In fact, this group was found to have significantly longer disease-free survival (p<.05).
In 1990, Lee et al.  retrospectively evaluated 143 patients with Stage I endometrial cancer . Of this group, a subset of 106 patients considered low-risk (grade 1 or 2, <1/2 myometrial invasion, and no metastases to nodes or other organs) were offered oral ERT. These patients were followed for at least two years (median follow-up time after initial cancer therapy was 87 months for estrogen users and 63 months for nonusers). The majority of the estrogen users (57%) started estrogen therapy within the first postoperative year, and had taken estrogen for >5 years (55%) at the time of data analysis. In the 44 estrogen-treated patients there were no recurrences and in the 62 other low risk nonestrogen-treated patients, one recurrence occurred. Again, in these low risk patients, no increase in recurrence rate was seen in the estrogen-treated group.
These studies, although small and retrospective, certainly suggest that ERT is safe in patients with a history of low risk, early stage endometrial cancer who have completed their cancer therapy. An American College of Obstetricians and Gynecologists (ACOG) Committee Opinion concluded that estrogen therapy may be used in patients with past endometrial cancer, although patient selection must be based on prognostic indicators . The need for adding progestational agents to estrogen therapy is unknown, but since progestins are known to antagonize the growth-promoting effects of estrogen on the endometrium, progestin addition seems reasonable, at least until larger, randomized trials are performed. Finally, more information is needed before recommendations can be made regarding estrogen doses, mode of estrogen therapy, and best time for initiating ERT after cancer treatment.
In conclusion, patients who have been treated for endometrial cancer and fall into a low risk group (stage I disease, grade 1 or 2, and <1/2 myometrial invasion) have a <5% recurrence rate regardless of whether or not ERT is given [5, 6]. The long term benefits of estrogen therapy including cardiovascular protection, a reduced risk of osteoporosis, and fewer vasomotor and other menopausal symptoms may outweigh the small risk of disease recurrence in these patients. In these selected patients, the contribution of ERT to the risk of recurrence is probably negligible.
1. Fisher ES, Baron JA, Malenka DJ, et al. Hip fracture incidence and mortality in New England. Epidemiology. 2:116-22 (1991)
2. Creasman, W. T., Henderson, D., Hinshaw, W., and Clarke-Pearson, D. L. Estrogen replacement therapy in the patient treated for endometrial cancer. Obstet. Gynecol. 67: 326-330 (1986).
3. Lee, R. B., Burke, T. W., Park, R. C. Estogen replacement therapy following treatment for stage I endometrial carcinoma. Gynecol. Oncol. 36: 189-194 (1990).
4. American College of Obstetricians and Gynecologists, Committee on Gynecologic Practice. Estrogen replacement therapy and endometrial cancer. ACOG Committee Opinion No. 126. Washington DC: American College of Obstetricians and Gynecologists (1993).
5. DiSaia, P.J., Creasman, W.T., Boronow, R.C., and Blessing, J.A. Risk factors and recurrent patterns in Stage I endometrial cancer. Am. J. Obstet. Gynecol.. 151: 1009-1015 (1985).
6. Creasman, W.T., Morrow, C. P., Bundy, B.N., Homesley, H.D., Graham, J.E., Heller, P.B. Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group Study. Cancer. 60: 2035-2041 (1987).