Unopposed Estrogen Replacement Therapy Research Articles

Gynecologic consequences of long-term, unopposed estrogen replacement therapy

We evaluated the gynecologic risks of unopposed, long-term estrogen use in postmenopausal women. Our medical record review showed that unopposed estrogen users (mean dose, 0.9 mg of conjugated estrogens) had a significantly higher ( P < 0.001) incidence of abnormal vaginal bleeding, curettage, hysterectomy, and endometrial cancer. The ratios of occurrence of these events among users compared with non-users were 7.8, 4.9, 6.6 and 7.7. The prevalence of hysterectomy reached 28.2% of users compared with 5.3% of non-users, and endometrial carcinoma developed in 9.9% of users compared with 1.4% of non-users.

Oestrogen-antioestrogen combination for post-menopausal replacement therapy

Post-menopausal women treated with sequential oestrogen-progestogen combinations usually experience regular uterine bleeding, which is unacceptable to most of them. It is especially unwelcome where the medication is administered for prophylactic purposes and the last menstruation occurred years previously. On the other hand, extended unopposed oestrogen replacement therapy for more than 2 yr is risky because of the possible development of endometrial carcinoma VI. To resolve this dilemma two forms of continuous replacement therapy have been developed:

The dose-effect relationship between 'unopposed' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk.

The 'unopposed oestrogen hypothesis' for endometrial cancer maintains that risk is increased by exposure to endogenous or exogenous oestrogen that is not opposed simultaneously by a progestagen, and that this increased risk is due to the induced mitotic activity of the endometrial cells. Investigation of the mitotic rate during the menstrual cycle shows that increases in plasma oestrogen concentration above the relatively low levels of the early follicular phase do not produce any further increase in the mitotic rate of endometrial cells. A modification of the unopposed oestrogen hypothesis which includes this upper limit in the response of endometrial cells to oestrogen is consistent with the known dose-effect relationships between endometrial cancer risk and both oestrogen replacement therapy and postmenopausal obesity; it also suggests that the mechanism by which obesity increases risk in premenopausal women involves progesterone deficiency rather than oestrogen excess, and that the protective effect of cigarette smoking may be greater in postmenopausal than in premenopausal women. Detailed analysis of the age-incidence curve for endometrial cancer in the light of this hypothesis suggests that there will be lifelong effects of even short duration use of exogenous hormones. In particular, 5 years of combination-type oral contraceptive use is likely to reduce a woman's lifetime risk of endometrial cancer by some 60%; whereas 5 years of unopposed oestrogen replacement therapy is likely to increase her subsequent lifetime risk by at least 90%; and even 5 years of 'adequately' opposed therapy is likely to increase subsequent lifetime risk by at least 50%.

Sex Steroids and Cancer

Hormones, particularly estrogens, have been suspected for many years of being carcinogens. Retrospective studies from the mid-1970s indicate that unopposed estrogen replacement therapy increases the risk for endometrial cancer. However, recent reports have failed to incriminate even unopposed estrogens for any significantly increased risk of breast cancer. Added progestogen, in proper duration and dosage, almost completely negates the estrogen-increased risk for adenocarcinoma of the endometrium. There is increasing evidence that progestogen added to estrogen replacement may decrease the risk for carcinoma of the breast in some women.

Prevention of endometrial cancer with progestogens

Unopposed oestrogen replacement therapy increases the risk of endometrial cancer in post-menopausal women. However, the addition of progestogen to the oestrogen therapy reduces the risk of endometrial carcinoma by preventing and effectively treating hyperplasia of the endometrium. In a 5-yr prospective study with a further 4 yr of follow-up (1975–1983), 31 adenocarcinomas of the endometrium were detected over 27243 patient-years of observation, for an incidence of 113.8:100000 women. The first report on the results of the study appeared in 1978; this paper presents further results. The lowest incidence of endometrial cancer (49.0:100000) was observed among the oestrogen-progestogen users and the highest (390.6:100000) among the unopposed oestrogen users. Not only was the incidence of endometrial carcinoma significantly lower in the oestrogen-progestogen users than in those using unopposed oestrogens ( P ⩽ 0.0001), but it was also significantly lower than that among the non-hormone users (245.5:100000 with P ⩽ 0.005). Endometrial hyperplasia had been diagnosed previously in 12 of the 31 patients with adenocarcinoma (38.7%) from 4 mth to 8 yr before the detection of cancer. When given for 7–10 days each month progestogens are effective in reversing hyperplasia and restoring a normal endometrium in 94.5% of patients treated within 3–6 mth. The progestogen challenge test was devised to identify post-menopausal women at greatest risk for adenocarcinoma of the endometrium. It is concluded that the use of this test will reduce the risk of endometrial cancer in both oestrogen-treated post-menopausal women and women with increased endogenous oestrogens.

Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: A comparison between progestogens and natural progesterone

Subfractions of high-density lipoprotein cholesterol and its apolipoproteins were followed up in 58 postmenopausal women during three cycles of unopposed estrogen replacement therapy with 2 mg of estradiol valerate daily. During the last 10 days of the following three cycles the women received sequential addition of either 250 μg of levonorgestrel, 10 mg of medroxyprogesterone acetate, or 200 mg of natural micronized progesterone. Both progestogens significantly decreased total high-density lipoprotein cholesterol as well as subfraction 2 of high-density lipoprotein. Data suggest that doses and relative biologic activity of 19-norsteroids and 17-hydroxyprogesterone derivatives are more important for their metabolic effects than are qualitative differences. Natural progesterone had no apparent influence on high-density lipoprotein cholesterol or its subfractions and may develop into an atractive alternative to synthetic progestogens.

Hormones in the etiology and prevention of breast and endometrial cancer.

Since the incidence of endometrial cancer among estrogen-treated women at Wilford Hall Air Force Medical Center was not increased as reported by others, a prospective study was begun in 1975. With this data base, the cases of breast and endometrial cancer in estrogen and oral contraceptive users were reviewed. The incidence of mammary malignancy in postmenopausal estrogen users (141.0:100,000) was lower than that of the untreated women, ie, nonhormone users (342.3:100,000) (P less than or equal to .01). The incidence of breast cancer in the estrogen-progestogen users (67.3:100,000) was significantly lower than that of the untreated women and than that expected from the Third National Cancer Survey (188.3:100,000) and the National Cancer Institute (NCI) data (229.2:100,000) (P less than or equal to .01). Oral contraceptives also decreased the risk of breast carcinoma, since the incidence in users (10.3:100,000) was significantly lower than expected in this age group according to both the Third National Cancer Survey (53.3:100,000) and the NCI data (57.3:100,000) (P less than or equal to .01). Unopposed estrogen replacement therapy increased the incidence of endometrial cancer to 410.8:100,000, but progestogen added to estrogen therapy significantly decreased this incidence to 68.1:100,000 (P less than or equal to .0001). The estrogen-progestogen users also had a significantly lower incidence of endometrial carcinoma than the untreated women (258.3:100,000) (P less than or equal to .005). Oral contraceptives, particularly the combination pill with estrogen and progestogen in each tablet, are protective against adenocarcinoma of the endometrium. The incidence of endometrial cancer apparently increased in premenopausal women during our study from 10.9:100,000 women in the first five years to 41.9:100,000 during the last two years as birth control pill use declined from 8,693 users in 1975 to 5,563 users during 1981, primarily in women over the age of 35.

Endometrial findings in asymptomatic postmenopausal women on exogenous estrogens—A preliminary report

Multiple retrospective studies have been done implicating estrogen replacement therapy as a factor in the increasing rise of endometrial cancer. This prospective study consisted of 94 asymptomatic postmenopausal females on exogenous estrogen. Duration of therapy ranged from 1 through 5 and greater than 5 years. All these patients were subjected to endometrial biopsies. We encountered a total of 71 negative biopsies (75.5%) and 23 positive biopsies (24.4%) ranging from cystic hyperplasia, through frank adenocarcinoma. All positive biopsies underwent formal diagnostic curettage. Histologic findings on the dilation and curettage specimens correlated with the original biopsy findings. All histologic slides were reviewed by an independent pathologist without knowledge of history or previous grading. Risk factors in the Positive biopsy group were present in only 17%. Therefore, it is not possible to predict the patient on estrogen who is at a higher risk for developing future hyperplasia, and in order to avoid missing early precursor lesions in endometrial carcinoma all patients must be biopsied. Significant cancer precursor lesions did not appear until after the patients had been on at least 3 years duration of unopposed estrogen replacement therapy. We conclude that postmenopausal patients on estrogen therapy at high risk can not be identified by risk factors alone, and as a minimum their endometrial status should be evaluated at least every 3 years.