Use of the progestogen challenge test to reduce the risk of endometrial cancer

In contrast to several retrospective studies reporting an increased risk of endometrial cancer during the mid-1970s, especially in estrogens.gen-treated postmenopausal women, the number of cancers at Wilford Hall USAF Medical Center has steadily declined despite continued estrogen use. In a 4-year study from 1975 to 1978, there were 17 adenocarcinomas of the endometrium during 10,872 patient-years of observation, for an overall annual incidence of 156.4:100,000 women. The highest incidence of endometrial cancer (359.1:100,000) was found in those women using estrogens alone. The lowest incidence of cancer was observed in the estrogen-progestogen users (56.4:100,000) and was significantly lower (P less than .01) than that found in the estrogen users. The incidence of corpus malignancy in the estrogen-progestogen users was also significantly lower (P less than .05) than that observed in the untreated women (248.3:1000,000). The progestogen challenge test has been devised to identify postmenopausal 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 estrogen-treated postmenopausal women and women with increased endogenous estrogens.     

Decreased incidence of breast cancer in postmenopausal estrogen-progestogen users

In a prospective study at Wilford Hall USAF Medical Center from 1975 to 1981, 5563 postmenopausal women were followed for a total of 37,236 patient-years of observation. During these seven years, 53 patients were found to have breast cancer, for an incidence of 142.3:100,000 women per year. The mean age (+/- SD) of the patients with cancer was 56.9 +/- 8.24 years, and the mean age of the entire patient population was 56.8 +/- 6.75 years. The expected incidence of breast cancer in this age group, according to the Third National Cancer Survey (1975), is 188.3:100,000 women, and for ages 55 to 59, according to the National Cancer Institute Surveillance, Epidemiology, and End-Result Reporting (NCI SEER) data (1980), is 229.2:100,000. The lowest incidence of breast cancer (67.3:100,000) was observed in the estrogen-progestogen users and was significantly lower than that of the untreated group (342.3:100,000), with P less than or equal to .01. The incidence of the estrogen-progestogen users was also significantly lower than that expected from the NCI SEER data, with a relative risk of 0.3 (95% confidence interval, 0.1 to 0.8). The incidence of mammary malignancy in the estrogen users (141.0:100,000) was significantly lower than in the untreated group (342.3:100,000), with P less than or equal to .01. Although the incidence in the estrogen users was not significantly lower than that expected according to the NCI SEER data (relative risk = 0.7, 0.5 to 1.1), there was a trend in that direction. These data indicate that estrogen therapy for postmenopausal women does not increase the risk of breast cancer and may afford some protection. Added progestogen to postmenopausal estrogen therapy significantly decreases the risk for this malignancy.     

Use of progestogens in postmenopausal women

Estrogen therapy for postmenopausal women has received adverse publicity since the mid-1970s because several reports linked estrogens with an increased risk of endometrial cancer. Other studies indicated that the risk of endometrial malignancy is reduced when a progestogen is added to the estrogen replacement. Not all postmenopausal women need estrogen replacement. Because some continue to produce significant amounts of endogenous estrogens, many need progestogen replacement to reduce the risk for endometrial hyperplasia and adenocarcinoma. It has been well demonstrated that estrogen replacement therapy does not increase the risk for breast cancer. However, added progestogen may actually reduce the risk for this malignancy in some women. Where estrogen therapy retards the development of and helps to prevent osteoporosis, added progestogen may restore bone which has been lost by promoting new bone formation. The greatest benefit to accrue to postmenopausal estrogen users is prevention of cardiovascular disease. Concern has been expressed that added progestogen may negate this benefit by adverse effects on lipids. Side effects of added progestogen occur, but these may be managed by changing to another progestogen or adding a mild diuretic.     

Cancer and the use of estrogens

Although unopposed estrogen therapy, as well as persistent or increased endogenous estrogens, increases the risk for endometrial hyperplasia and cancer, added progestogen decreases the risk for adenocarcinoma of the endometrium to less than that observed in untreated women. The progestogen challenge test should be administered to all postmenopausal women with an intact uterus--including estrogen-treated postmenopausal women and those with sufficient endogenous estrogens to remain asymptomatic--and the progestogen continued for 13 days each month for as long as withdrawal bleeding results. Estrogen replacement therapy should not be withheld from postmenopausal women who are estrogen deficient, since there is no evidence that estrogens increase the risk for breast cancer. Progestogen added to estrogen replacement significantly reduces the risk for mammary malignancy; therefore, progestogens should be given, even to women who have had a hysterectomy, for 10 to 13 days each month whenever they are prescribed estrogen therapy.     

Estrogens, progestogens and endometrial cancer.

At the Wilford Hall U.S. Air Force Base Medical Center, Texas, about 4000 postmenopausal women received estrogen replacement therapy during 1975. Of these, 2700 took estrogens only and 1240 were given a progestogen along with estrogen. Hysterectomy had been done previously on 1700 patients (42%), leaving 2300 with intact uteri and a risk of endometrial cancer. Adenocarcinoma of the endometrium was diagnosed in 7 patients. Of these, 6 had received estrogen therapy. There was 1 endometrial malignancy in a patient also receiving a progestogen. Among 510 untreated postmenopausal women with intact uteri, 1 adenocarcinoma of the endometrium was found. Type and dosage of estrogen were unrelated to endometrial malignancy. In addition to the 7 endometrial cancers from the clinic, 22 cases were diagnosed elsewhere and referred for treatment, 11 of these had received no hormones. 10 were taking estrogens and 1 was receiving Oracon for birth control. The incidence of endometrial malignancy in the U.S. is reported to be 21/100,000 women/year. There is a 3-fold to 9-fold increased risk of endometrial cancer associated with obesity alone. The probability that untreated postmenopausal women with intact uteri will develop carcinoma of the endometrium is 1/1000/year. With estrogen users, it is reported to be increased -7.6/1000 women/year. In the author's clinic during 1975, the incidence among those receiving only estrogen was 4.7/1000. Among those also receiving a progestogen the incidence was .8/1000. Unopposed estrogens apparently have a role in the etiology of endometria hyperplasia and neoplasia through incomplete shedding of the endometrium. Progesterone produces more complete sloughing of the endometrium and also converts all degrees of hyperplasia into secretory endometrium. Nulliparity, infertility, and anovulation are predisoposing factors to endometrial carcinoma. Progestogens are palliative therapy for endometrial cancer.     

The role of hormones in the etiology and prevention of endometrial cancer

Unopposed estrogens, both exogenous and endogenous, increase the risk of endometrial cancer although the magnitude of the association between estrogen replacement therapy and adenocarcinoma has been exaggerated by the epidemiologic case-control studies. Not all postmenopausal women need estrogen replacement therapy since some produce sufficient endogenous estrogens to remain asymptomatic and prevent atrophic vaginitis, osteoporosis and atherosclerosis. However, within this group may be those at risk for endometrial cancer, so they need to be identified and treated with cyclic progestogens. Sequential oral contraceptives did not protect young women from adenocarcinoma of the endometrium because of too little progestogen for too short a duration in view of the relatively high dosage of estrogen. However, combination birth control pills significantly decrease the risk for endometrial carcinoma. Endometrial hyperplasia is a precancerous lesion in some women and can be effectively reversed with 10-13 days of progestogen monthly in at least 98% of patients. The progestogen challenge test has been devised to identify postmenopausal women at greatest risk for adenocarcinoma. It should be administered to all postmenopausal women with an intact uterus. This includes asymptomatic women, patients receiving estrogen replacement therapy and women being evaluated for hormone therapy. If there is a positive response to the progestogen challenge, as manifested by withdrawal bleeding, then the progestogen should be continued for 13 days each month for as long as withdrawal bleeding results. If there is no response then the progestogen challenge test should be repeated at each annual examination. Universal use of the progestogen challenge test should prevent nearly all endometrial cancers.     

Doubts about oestrogen therapy in postmenopausal women

In postmenopausal women, the predominate steroid is estrone, and data have indicated that conversion of androgen to estrone is 2-3 times greater in women with endometrial cancer than in others. 2 studies of exogenous estrogens in postmenopausal women are summarized. In the 1st, 317 patients with adenocarcinoma were compared with matched controls with cervical, ovarian, and vulval neoplasms. 152 patients had estrogen therapy as compared with 54 controls, and calculations revealed the cancer risk as 4.5 times greater among patients than controls. The 2nd study concerned the use of conjugated estrogens. 94 patients with endometrial cancer and double that number of matched controls were examined. Conjugated estrogens had been used by 57% of patients and only 15% of controls. The data revealed an increased risk of 5.6 times in patients using estrogen for between 1 and 5 years, rising to 13.9 times greater risk after 7 or more years; and this relationship could not be explained by factors such as age, parity, obesity, or menopausal age. The chance of endometrial cancer in postmenopausal women not using estrogens is 1/100,000/year. In estrogen users, the level increases to between 4 and 8/100,000/year. More information is needed on effects of estrogens; they are valuable in relieving psychological symptoms, vasomotor instability, and, perhaps, mortality, osteoporosis, fractures, and vascular diseases after oophorectomy. These advantages have to be weighed against thromboembolism, coronary diease, strokes, and possible cancer; the benefits and risks are not easily calculated.     

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.     

Review of the endometrial effects of estrogens and progestins.

Several controversial areas have been reviewed. It would seem from the evidence at hand that progression from endometrial hyperplasia to endometrial carcinoma does occur in a significant percentage of women and that endometrial hyperplasia, particularly adenomatous hyperplasia and atypical hyperplasia, must be regarded as premalignant changes. Gambrell believes that all stages of hyperplasia should be regarded as premalignant. Previous and retrospective studies provide evidence implicating estrogens in the causation of both endometrial hyperplasia and endometrial carcinoma. Although some of these studies may have design flaws, the amount of data is substantial. Prospective studies have demonstrated an increased risk of hyperplasia in women treated with estrogens. An increased risk of endometrial carcinoma in estrogen users compared with nonusers has been suggested even more recently. Reviewed as a whole, the cumulative evidence provided by these studies clearly supports this association, and it would appear the only issue left to resolve may be the magnitude of the association. Cyclic administration of estrogens may decrease the risk of development of endometrial carcinoma. It would seem, however, that such administration does not totally eliminate risk under any circumstances, and in fact, a dose-related relationship appears to persist. It seems well established that progestogens do decrease the risk of both endometrial hyperplasia and endometrial carcinoma associated with the administration of estrogen to peri- and postmenopausal women. Such reduction in risk is significant and lower relative risks in estrogen/progestogen treated women have been reported compared to untreated women. This reduction in risk has been reported in a variety of studies. Whitehead and co-workers have provided a clear biochemical mechanism for progestogen protection of the endometrium in the antagonism of estrogen at the endometrial cellular level. The evidence at hand in the literature would suggest that progestogens should be administered for at least 10 days per cycle. In summary, there is good evidence that the addition of a progestin to estrogen therapy prescribed for the symptoms of menopause provides protection from endometrial hyperplasia and related carcinoma. The protection conferred is greater than that afforded by cyclical estrogen-alone therapy, and allows for continuous therapy, hereby providing greater symptomatic relief. There is little evidence for adverse effects caused by the added progestins, but further studies of women on combined therapy will undoubtedly be warranted.     

Association of estrone with the development of endometrial carcinoma.

Although few clinicians suspect estrogen as the prime cause of endometrial carcinoma, a retrospective study showed the following among postmenopausal women: 70 per cent of those with endometrial carcinoma and only 23 per cent of matched control subjects used estrogen systemically. Endometrial cancer developed an average of five years earlier in those taking than in those not receiving estrogen. Forty-two per cent of those with endometrial cancer had received estrogen three years or more. Most significantly, conjugated estrogens were used by 89 per cent of postmenopausal cancer patients who had received any estrogenic substance. The increased risk of endometrial cancer for all patients receiving conjugated estrogen (the risk ratio) was 7.4. This risk ratio increased with duration of conjugated estrogen exposure, from 4.6 in patients with less than three years' exposure to 9.2 in patients with three or more years' exposure.     

Changes in lipids and lipoproteins with long-term estrogen deficiency and hormone replacement therapy

Cross-sectional data of the long-term effects of estrogens, androgens, and progestogens on lipids and lipoproteins were obtained in 556 postmenopausal women aged 24 to 85 years with follow-up for 1 to 44 years. Baseline values were obtained in 155 women from less than 1 year up to 30 years after menopause. Total cholesterol and low-density lipoprotein cholesterol tended to rise during the early postmenopausal years while high-density lipoprotein cholesterol did not change. Triglycerides were related to weight and were significantly different only between untreated women of normal weight (128.3 +/- 7.80 mg/dl) and hormone users weighing greater than 200 pounds (252.9 +/- 9.44 mg/dl), p less than or equal to 0.001. Although mean high-density lipoprotein cholesterol was lower with both C-21 progestogens (64.5 +/- 4.16 mg/dl) and C-19 progestogens (61.9 +/- 3.84 mg/dl), there were no statistically significant differences on comparison with levels in the unopposed estrogen users (67.0 +/- 3.94 mg/dl). Smoking significantly depressed high-density lipoprotein cholesterol in both hormone users (p less than or equal to 0.001) and untreated women (p less than or equal to 0.001). Added progestogens do not adversely affect lipids and lipoproteins over the long term when adequate dosages of estrogens are used.     

Continuous combined hormone replacement therapy and risk of endometrial cancer

OBJECTIVE: Postmenopausal women who receive sequential hormone replacement therapy with estrogen combined with progestogen for 10 to 24 d/mo for a prolonged period may have an elevated endometrial cancer risk relative to those who have never received hormone replacement therapy. We investigated whether daily use of estrogen and progestogen (continuous combined hormone replacement therapy) could diminish any excess endometrial cancer risk.Study Design: A population-based study in Washington State obtained interview data from 969 women aged 45 to 74 years with endometrial cancer diagnosed during 1985 through 1991 or 1994 through 1995 and from 1325 age-matched control subjects selected primarily by random digit dialing. Women who had received only continuous combined hormone replacement therapy were compared with women who had only received another hormone replacement therapy regimen or who had never received hormone replacement therapy. RESULTS: The risk of endometrial cancer among users of continuous combined hormone replacement therapy (n = 9 case patients, n = 33 control subjects) relative to women who had never received hormone replacement therapy was 0.6 (95% confidence interval, 0.3-1.3); the risk relative to women who received hormone replacement that included progestogen for 10 to 24 d/mo was 0.4 (95% confidence interval, 0.2-1.1). Most continuous combined hormone replacement therapy use was short-term (<72 months) or recent (in the previous 24 months). CONCLUSION: Women who had received continuous combined hormone replacement therapy for several years did not appear to be at any increased risk for endometrial cancer relative to women who had never received hormone replacement therapy and may in fact be at decreased risk for endometrial cancer.     

Estrogen therapy arrests bone loss in elderly women

Although osteoporosis is an age-related disorder, the accelerated bone loss observed in postmenopausal women may be preventable with early diagnosis and adequate estrogen replacement. In a prospective study, we investigated the effect of oral estrogen replacement using conjugated estrogens (Premarin, 0.625 mg) or micronized 17 beta-estradiol (Estrace, 1 mg) versus no estrogen in sequential single-photon bone density measurements over 3-year intervals in 397 postmenopausal women. Estradiol, 1 mg, and conjugated estrogens, 0.625 mg, were equally effective in regarding bone loss. The rate of bone loss was about the same for estrogen users regardless of age (51 to 80 years) and was approximately one third that of nonusers. Among nonusers a uniform accelerated rate of bone loss of 2.5% per year was noted between 56 and 70 years old, whereas between the ages of 51 and 55 years and after age 70 years, the rate of bone loss was significantly less. Ever users over age 65 years showed continued protection from bone loss as long as estrogen therapy was continued. Previous estrogen users who stopped estrogen after age 65 years lost bone more rapidly than women of similar age who had never taken estrogen. Thus to prevent accelerated bone loss in postmenopausal women, we recommend early and continued hormone replacement for life. Estrogen nonusers should be monitored at regular intervals to minimize accelerated bone loss.     

Dose of progestin in postmenopausal-combined hormone therapy and risk of endometrial cancer

OBJECTIVE: We studied the impact of progestin dose on this risk. The pattern and number of days per month that progestin is given in postmenopausal combined hormone therapy appears to affect endometrial cancer risk. We assessed the impact of progestin dose on this risk. STUDY DESIGN: A population-based, case-control study included 647 cases with endometrial cancer and 1209 controls. RESULTS: Among users of estrogen with medroxyprogesterone acetate (MPA) 10 to 24 days/month, women who took >100 mg/month had an endometrial cancer risk that was equal to that of hormone nonusers (95% CI 0.6-1.7). The corresponding relative risk was 0.8 (95% CI 0.5-1.5) in those who used a lower monthly MPA dose for 10 to 24 days/month. Among users of a continuous combined hormone regimen, the risk of endometrial cancer was low relative to hormone nonusers, regardless of MPA dose. CONCLUSION: Among the combined hormone regimens most commonly used by postmenopausal women today, MPA monthly dose bears little or no relation to endometrial cancer risk.     

Role of estrogens and progesterone in the etiology and prevention of endometrial cancer: review

Our present knowledge of the role of sex steroids in the development as well as the prevention of endometrial cancer is reviewed. Factors which increase the exposure of the uterus to unopposed estrogens, either exogenous or endogenous, are associated with increased risk of endometrial adenocarcinoma. However, there is increasing evidence that progestogens can reverse endometrial hyperplasia and protect against the development of endometrial cancer. The mechanisms to explain the antiestrogenic effects of progestogens include changes in enzyme activity and steroid receptors in endometrial tissue. Postmenopausal women treated with combined estrogen and progestogen have the lowest incidence of endometrial carcinoma. Oral contraceptives containing both estrogen and progestogen in each tablet are protective against adenocarcinoma of the endometrium, while the sequential oral contraceptive pills afforded less protection. The risks and benefits of these hormone therapies are discussed in relation to the etiology and prevention of endometrial cancer.     

Comparative cardiovascular effects of different progestins in menopause.

Progesterone receptors are present in the arterial wall and it is, therefore, likely that the arterial effects of progestins are mediated through progesterone receptors as well as through down-regulation of the estradiol receptor. Progestin therapy affects arterial function, as it can stabilize arteries in a state of vasomotor instability, but may also induce vasoconstriction of estrogenized vessels. Thus, the cardiovascular effects of progestins may influence the cardioprotective effect of estrogens. There has been some concern that a combined estrogen-progestogen therapy may attenuate some of estrogen's beneficial effects on cardiovascular health. This is a reflection of the past epidemiologic studies which have used primarily unopposed estrogen. The PEPI trial is the only large-scale, long-term study to compare directly the effects of different combined hormone replacement therapy regimens upon plasma lipids in healthy women. This study has shown that the adjunctive clinical impact of different progestogens on the beneficial effect of estrogen replacement therapy is trivial. It has never been proved that in normocholesterolemic women, e.g., those included in the PEPI trial, the increase in HDL reduces cardiovascular mortality or morbidity. Based on the results of PEPI, hormone replacement therapy has positive effects on key heart disease risk factors and endometrial tissue, and the magnitude of those effects does not differ significantly across the hormone replacement therapy regimens used. At present there are only few and inconclusive data available on the vascular effect of progestins in menopausal women. Some studies found that progestins reduced the beneficial effect of estrogens, while others did not. Our group has recently shown that different estrogen-progestin treatments have different effects upon vascular reactivity and that a careful selection of the progestin to be added to estrogen is of capital importance to preserve, or even enhance the positive vascular effects of estrogens. Few epidemiological studies have investigated the effect of adding a progestin to estrogen therapy upon cardiovascular mortality and morbidity, and all have suggested that hormone replacement therapy may be more effective than estrogen replacement alone in reducing cardiovascular events in primary prevention. The results of the recently published Heart and Estrogen/progestin Replacement Study (HERS) have added some critical data on the effect of hormone replacement therapy for secondary prevention in women with coronary artery disease. The study, however, is affected by several important methodological and statistical problems, which make its interpretation difficult and its conclusions useless for clinical practice. The results of the study should be evaluated with caution by physicians who give advice on hormone replacement therapy, and no woman should be taken off hormone replacement therapy because of HERS. Of importance, the results of HERS should not be used to suggest alternative forms of treatment, especially the selective estrogen receptor modulators (SERMs), for cardiovascular protection in postmenopausal women.     

Endometrial disease after treatment with oestrogens and progestogens in the climateric (author's transl)

This study was undertaken to examine the frequency of histologic endometrial anomalies with different types of estrogen therapy, whether or not associated to progesterone treatment. 1002 endometrial biopsies were done on 745 women who had received: 1) cyclic treatment with low-dose estrogen; 2) cyclic treatment with high-dose estrogen; 3) sequential estrogen-progestogen treatment; and 4) subcutaneous implant of estradiol. Frequency of abnormalities was 7.0% in the first group, 14.8% in the second group, 1.2% in the third group, and 14.8% in the fourth group. Without drawing definitive conclusions from these results, it seems possible to affirm that the use of progestogen diminishes the risk of endometrial cancer during menopause.     

Transvaginal ultrasonographic assessment of the endometrium in asymptomatic, postmenopausal women using different HRT regimens containing tibolone or estrogen

OBJECTIVE: To assess the effects of hormone replacement therapy (HRT) on endometrial thickness as measured by transvaginal ultrasonography in asymptomatic, postmenopausal women. STUDY DESIGN: Between 1997 and 2001, 307 women who had no risk factors for endometrial cancer or abnormal vaginal bleeding were enrolled in a study. Patients received 1 of the following HRT modalities: (1) oral equine HRT modalities: (1) oral equine estrogen, (2) oral 17beta-estrogen, (3) transdermal 17beta-estrogen, or (4) oral tibolone. All women taking estrogens were also taking a progestin. Only the patients with endometrial thickness >7 mm underwent endometrial biopsy while taking HRT. RESULTS: Although we observed an increase in serum estrogen levels as compared to the levels before tibolone therapy, changes in endometrial thickness were not statistically significant in patients taking tibolone. CONCLUSION: Endometrial thickness with tibolone closely mimics the naturally atrophic postmenopausal state. Thus, tibolone is suggested for those postmenopausal women who have concerns about HRT.     

Differential effects of thiazide and estrogen upon bone mineral content and fracture prevalence

Individual and combined effects of thiazides and estrogens upon bone mineral content at four sites (proximal radius, distal radius, os calcis, lumbar spine) and fracture prevalence were assessed retrospectively in 993 postmenopausal women. Compared with untreated women, use of thiazide alone was associated with significantly higher bone mineral content (P less than or equal to .01); nonspine fracture prevalence in this group was reduced by one-half (P = .07). Estrogen alone also was associated with significantly higher bone mineral content (P less than or equal to .0001); nonspine fracture prevalence was reduced by almost one-half (P = .07). The users of both estrogen and thiazide had the highest bone mineral content levels, which were significantly different than the thiazide-only group at four bone sites (P less than or equal to .001), and the estrogen-only group for three bone sites (P less than or equal to .05). Nonspine fracture prevalence for the users of both drugs was 17% that of the untreated group (P = .02). The relationships with spine fracture prevalence were less consistent; however, estrogen users appeared to have a lower spine fracture prevalence rate and higher spinal bone mineral content than thiazide users. These findings suggest a potential role for thiazides in the prevention of osteoporosis.