Estrogen replacement therapy in the patient treated for endometrial cancer

Adenocarcinoma of the endometrium is considered to be an estrogen-dependent neoplasia and as such, hormone replacement therapy is said to be contraindicated. The authors are unaware of any data to substantiate that statement. Patients, who had completed their therapy for stage I carcinoma of the endometrium, were placed on estrogen hormone replacement therapy in a nonrandomized fashion. Between 1975 and 1980, 221 patients with stage I adenocarcinoma of the endometrium were managed at the Duke University Medical Center. Forty-seven patients received estrogen after their cancer therapy, whereas 174 patients did not. Risk factors for recurrence were similar between the two groups. After controlling for these known risk factors, the estimated distributions of time to recurrence for the two groups were significantly different (P less than .05), with the estrogen group experiencing longer disease-free survival. The history of endometrial cancer does not appear to be a contraindication to hormone replacement therapy in patients with stage I disease.     

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.     

Persistence of endometrial activity after radiation therapy for cervical carcinoma

Radiation therapy is a proved treatment for cervical carcinoma; however, it destroys ovarian function and has been thought to ablate the endometrium. Estrogen replacement therapy is often prescribed for patients with cervical carcinoma after radiation therapy. A review of records of six teaching hospitals revealed 16 patients who had endometrial sampling for uterine bleeding after standard radiation therapy for cervical carcinoma. Fifteen patients underwent dilatation and curettage, and one patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy when a dilatation and curettage was unsuccessful. Six patients had fibrosis and inflammation of the endometrial cavity, seven had proliferative endometrium, one had cystic hyperplasia, one had atypical adenomatous hyperplasia, and one had adenocarcinoma. Although the number of patients who have an active endometrium after radiation therapy for cervical carcinoma is not known, this report demonstrates that proliferative endometrium may persist, and these patients may develop endometrial hyperplasia or adenocarcinoma. Studies have indicated that patients with normal endometrial glands have an increased risk of developing endometrial adenocarcinoma if they are treated with unopposed estrogen. Patients who have had radiation therapy for cervical carcinoma should be treated with estrogen and a progestational agent to avoid endometrial stimulation from unopposed estrogen therapy.     

Controversies concerning the safety of estrogen replacement therapy

Unopposed estrogen replacement is known to cause endometrial carcinoma in a small percentage of postmenopausal women, but the effects on ovarian and breast tissue remain uncertain. The increased risk of endometrial carcinoma seems to be related to both the dosage and duration of unopposed estrogen treatment. Until very recently, the morbidity and costs that result from the need for endometrial biopsy because of abnormal bleeding and from the need for hysterectomy due to hyperplasia have been ignored, but recent data suggest that they are likely to be considerable. Progestogens are known to protect against endometrial hyperstimulation, but the optimal duration of therapy each month and the maximally protective agent and dose remain to be determined. Estrogen replacement therapy may reduce the risk of arterial disease; however, the comparative effects of the various preparations, as well as their respective mechanisms of action, must be subjected to further study.     

Estrogen replacement therapy in patients with early breast cancer

OBJECTIVE: Most physicians believe that estrogen replacement therapy is contraindicated once a patient is diagnosed with breast cancer. Recently, several studies have shown that estrogen replacement therapy may be safely used in patients with early breast cancer that has been treated successfully. These women can have severe menopausal symptoms and are at risk for osteoporosis. We reviewed the current status of women in our practice with breast cancer who received estrogen replacement therapy, who did not receive hormone replacement therapy, and who did not receive estrogenic hormone replacement therapy. STUDY DESIGN: The study group consisted of 123 women (mean age, 65.4 +/- 8.85 years) who were diagnosed with breast cancer in our practice, including 69 patients who received estrogen replacement therapy for < or = 32 years after diagnosis. The comparative groups were 22 women who used nonestrogenic hormones for < or = 18 years and 32 women who used no hormones for < or = 12 years. The group who did not receive estrogenic hormone replacement therapy received androgens with or without progestogens (such as megestrol acetate). Of the 63 living hormone users, 56 women are still being treated in our clinic, as are 15 of the 22 subjects who receive nonestrogenic hormone replacement therapy. Follow-up was done through the tumor registry at University Hospital; those patients whose tumor records were not current were contacted by telephone. RESULTS: There were 18 deaths in the 123 patients: 6 patients who received estrogen replacement therapy (8.69%), 2 patients who received nonestrogenic hormone replacement therapy (9.09%), and 10 patients who received no hormone replacement therapy (31.25%). Of the 18 deaths, 9 deaths were from breast cancer (mortality rate, 7.3%); 3 deaths were from lung cancer; 1 death was from endometrial cancer; 1 death was from myocardial infarction; 1 death was from renal failure; and 3 deaths were from cerebrovascular accidents. The 9 deaths from breast cancer included one patient who received nonestrogenic hormone replacement therapy (mortality rate, 4.5%), 6 patients who received no hormone replacement therapy (mortality rate, 11.3%), and 2 patients who received estrogen replacement therapy (mortality rate, 4.28%). The 9 non-breast cancer deaths included 4 patients who received estrogen replacement therapy (endometrial cancer [1 death], lung cancer [1 death], cerebrovascular accident [1 death], and renal failure [1 death]), 1 patient who did not receive estrogenic hormone replacement therapy group (myocardial infarction), and 4 patients who used no hormones (lung cancer, 2 deaths; stroke, 2 deaths). Carcinoma developed in one patient in the estrogen replacement therapy group in the contralateral breast after 4 years of hormone replacement therapy; she is living and well 2.5 years later with no evidence of disease. Metastatic breast cancer developed in one patient after 8 years of hormone replacement therapy; she is living with disease. CONCLUSION: Estrogen replacement therapy apparently does not increase either the risk of recurrence or of death in patients with early breast cancer. These patients may be offered estrogen replacement therapy after a full explanation of the benefits, risks, and controversies.     

Hormone replacement therapy in women with past history of endometriosis.

Endometriosis is a common clinical condition and its treatment will often lead to an estrogen deficiency status. As most of these patients are young, they will need to consider hormone replacement therapy. Endometriosis is a hormone-dependent disease and estrogen replacement can be associated with a risk of recurrence or malignant transformation. Only a few studies have addressed this problem. With the use of hormone replacement therapy (HRT), there is an increased, although undefined, risk of recurrence of endometriosis, especially in known severe cases and in obese patients. Unopposed estrogen appears to carry a higher risk than combined preparations. Delay in starting HRT after pelvic clearance is not of any benefit. After radical surgery for severe endometriosis, women often have much to gain from HRT, particularly in the early years. Benefits of HRT in terms of control of menopausal symptoms, prevention of urogenital atrophy and loss of libido and bone protection are of particular importance. HRT may still have a role in prevention of cardiovascular disease in early menopause, but this remains unproven. Although there is no firm evidence, continuous combined preparations or tibolone would appear to be the optimum choice.     

Estrogen replacement therapy following treatment for stage I endometrial carcinoma

One hundred forty-four patients with clinical stage I endometrial adenocarcinoma were treated over an 11-year period at Madigan Army Medical Center and Brooke Army Medical Center. Following surgical staging, 44 selected patients were placed on oral estrogen replacement for a median duration of 64 months. In the estrogen user group, there were no recurrent endometrial cancer and no intercurrent death. Of the 99 nonestrogen users, there were 8 recurrences (8%) and 8 intercurrent deaths. Patients placed on estrogen replacement had low-risk factors for recurrence, namely, low tumor grade (grades 1 and 2), less than 1/2 myometrial invasion, and no metastases to lymph nodes or other organs. Postoperative estrogen replacement appears to be safe in selected low-risk patients.     

Recurrent benign metastasizing leiomyoma after hysterectomy and bilateral salpingo-oophorectomy

BACKGROUND: Benign uterine leiomyomas are sometimes found in association with benign smooth muscle tumors outside the confines of the uterus and are given the name benign metastasizing leiomyomas (BML). We present two patients who were on estrogen replacement therapy, in which BML recurred twice despite previous hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) requiring two additional laparotomies. PATIENTS: Our patients, presented with multiple abdominal masses 6 years after their initial surgery for benign leiomyoma. At exploratory laparotomy multiple benign leiomyomas were resected, and in one case a 2.2 cm leiomyoma was also resected from the left lower lobe of the lung. Both patients had a third laparotomy for another abdominal recurrence approximately 2 years later. RESULTS: Pathology revealed benign leiomyomas with no cytological atypia and a mitotic count of <5 per 10 high power fields (hpf). CONCLUSION: Benign metastasizing leiomyoma rarely follow TAH/BSO in patients with uterine myoma and estrogen replacement therapy may play a role in such occurrence. Despite surgery to remove these tumors, they can still recur; therefore, there is need for prolonged surveillance in such patients after resection.     

Estrogen replacement therapy: is previously treated cancer a contraindication?

The benefits of estrogen replacement therapy in preventing vasomotor symptoms, osteoporosis, and cardiovascular disease are well documented. Although estrogen is said to be contraindicated in patients successfully treated for endometrial and breast cancer, there are no data to substantiate this admonition. Experience suggests that it can be used safely in patients treated previously for endometrial cancer. Although there is little or no experience with estrogen use in the woman treated previously for breast cancer, circumstantial evidence suggests that it is not contraindicated in all such cases. Informed consent, patient desires, and risk-benefit considerations must enter into the decision to use estrogen in these patients.     

Port site recurrences following laparoscopically managed early stage endometrial cancer

Faught W, Fung Kee Fung M. Port site recurrences following laparoscopically managed early stage endometrial cancer. Int J Gynecol Cancer 1999; 9: 256–258.
Laparoscopic management of endometrial cancer, although gaining in acceptance, has been associated with recurrent disease at trocar insertion sites in advanced disease. We report on a patient with a port site recurrence in early stage endometrial cancer.
An 84-year-old patient with cancer of the endometrium underwent a laparoscopic surgical staging, vaginal hysterectomy, and adjunct radiation treatment. The final surgical pathology was grade 3, stage IC endometrioid adenocarcinoma. Seven months post-treatment, she presented with bilateral port site recurrences in the lower abdominal wall.
Trocar port site recurrence in gynecologic cancer patients may be enhanced by laparoscopic management and are not limited only to patients with advanced disease.     

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.     

Estrogen replacement therapy in endometrial cancer patients: a matched control study

OBJECTIVE: To determine if estrogen replacement therapy, in women with a history of endometrial cancer, increases the risk of recurrence or death from that disease. METHODS: Two hundred forty-nine women with surgical stage I, II, and III endometrial cancer were treated between 1984 and 1998; 130 received estrogen replacement after their primary cancer treatments and 49% received progesterone in addition to estrogen. Among this cohort, 75 matched treatment-control pairs were identified. The two groups were matched by using decade of age at diagnosis and stage of disease. Both groups were comparable in terms of parity, grade of tumor, depth of invasion, histology, surgical treatment, lymph node status, postoperative radiation, and concurrent diseases. The outcome events included the number of recurrences and deaths from disease. RESULTS: The hormone users were followed for a mean interval of 83 months (95% confidence interval [CI] 71.0, 91.4) and the nonhormone users were followed for a comparable mean interval of 69 months (CI 59.1, 78.7). There were two recurrences (1%) among the 75 estrogen users compared with 11 (14%) recurrences in the 75 nonhormone users. Hormone users had a statistically significant longer disease-free interval than nonestrogen users (P =.006). CONCLUSION: Estrogen replacement therapy with or without progestins does not appear to increase the rate of recurrence and death among endometrial cancer survivors.     

Estrogen replacement therapy: its benefits and risks

A carefully taken history and clinical examination are necessary for assessing the relative benefits and risks of estrogen replacement therapy for an individual patient. The patient's weight, blood pressure and urine need to be checked. Benefits of estrogen replacement are seen in relation to vasomotor symptoms, atrophy of the genital tract, bone metabolism, psychological symptoms, libido, skin, and cardiovascular effects. Estrogens are contraindicated with a history of previous deep vein thrombosis, ischemic heart disease or carcinoma of the breast. Care needs to be taken with liver disease, hyperlipidemias, diabetes, gallbladder disease, gross obesity, or in heavy smokers. Progesterones should always be administered if the uterus is present to prevent endometrial hyperplasia and adenocarcinoma. When properly selected and carefully monitored, many women may be relieved of unnecessary suffering due to menopause.     

Use of progestogen therapy

Estrogen therapy for postmenopausal women has received adverse publicity since the mid-1970s because several reports implicated 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. Not all postmenopausal women need estrogen replacement, since many are symptom free because they continue to produce endogenous estrogens. Within this group may be the women at greatest risk for adenocarcinoma of the endometrium. The progestogen challenge test was devised to identify women at greatest risk for endometrial cancer. The number of endometrial malignancies declined at Wilford Hall U.S. Air Force Medical Center with increasing use of this test from 1975 through 1983. The lowest incidence of endometrial cancer was observed in the estrogen-progestogen users (49.0 per 100,000) and was significantly lower than that found in either the unopposed estrogen users (390.6 per 100,000; p less than or equal to 0.0001) or in the untreated women (245.5 per 100,000; p less than or equal to 0.005). The incidence of breast cancer was also significantly lower in the estrogen-progestogen users (66.8 per 100,000) than in the untreated group (343.5 per 100,000) and lower than that expected from two national cancer surveys (188.3 and 229.2 per 100,000; p less than or equal to 0.01). Progestogens should be added to estrogen replacement therapy in women who have undergone a hysterectomy, as well as in those with an intact uterus.     

Menopause: advanced management strategies.

Estrogen replacement therapy may offer significant benefits to nearly all postmenopausal women, especially those for whom the menopause occurred at an early age. Women at high risk for atherosclerosis, or who already have cardiovascular disease, may particularly benefit from estrogen use. The increased risk for endometrial and breast cancer seen with estrogen replacement therapy is low in comparison with its protective effect against cardiovascular disease. For women who cannot or choose not to take estrogens, etidronate may be of value in preventing osteoporotic fractures. For women many years beyond menopause who consume low-calcium diets, calcium supplementation should be recommended.     

A successful live birth with in vitro fertilization and thawed embryo transfer after conservative treatment of recurrent endometrial cancer

Estrogen-dependent early stage endometrial cancer is relatively common in young women of reproductive age. The standard treatment is hysterectomy and bilateral salpingo-oophorectomy (BSO), even in early stage well-differentiated endometrial cancer patients. This surgical option results in permanent loss of fertility. There have been some reports of live births using in vitro fertilization after conservative management of endometrial cancer with high-dose progestin for the purpose of fertility preservation. However, most were not recurrent cases and pregnancy was achieved through conventional in vitro fertilization, which usually raises serum estradiol levels and may lead to the recurrence of endometrial cancer. To date, it is hard to find a case that can be referred for any possible different approach needed for the patients who experience recurrence. Here we report a successful live birth with in vitro fertilization using letrozole to maintain physiological levels of estradiol, and subsequent thawed embryo transfer after elective cryopreservation of embryos in a patient with recurrent endometrial cancer. There has been no evidence of disease recurrence at one year after delivery.     

Endometrial patterns and endocrinologic characteristics of asymptomatic menopausal women

The endometrial histology and endocrinologic and demographic characteristics of 556 asymptomatic postmenopausal women ,who attended the menopause outpatient clinic at Ankara Numune Education and Research Hospital were studied before initiating estrogen replacement therapy. Of these women ,486 (87.4%) had atrophic endometrium ,37 (6.65%) had proliferative endometrium ,27 (4.86%) had endometrial hyperplasia without atypia ,three (0.54%) had endometrial hyperplasia with atypia and three (0.54%) had endometrial adenocarcinoma on their biopsy specimens. When demographic characteristics of the patients were considered, we found that the patients with endometrial adenocarcinoma and endometrial hyperplasia with atypia had potential risk factors for endometrial pathology such as chronic anovulation ,diabetes or hypertension. This study confirms that routine endometrial sampling in asymptomatic postmenopausal women is not warranted ,but patients with associated risk factors should be screened for endometrial pathology before starting estrogen replacement therapy.     

Endometrial patterns and endocrinologic characteristics of asymptomatic menopausal women.

The endometrial histology and endocrinologic and demographic characteristics of 556 asymptomatic postmenopausal women, who attended the menopause outpatient clinic at Ankara Numune Education and Research Hospital were studied before initiating estrogen replacement therapy. Of these women, 486 (87.4%) had atrophic endometrium, 37 (6.65%) had proliferative endometrium, 27 (4.86%) had endometrial hyperplasia without atypia, three (0.54%) had endometrial hyperplasia with atypia and three (0.54%) had endometrial adenocarcinoma on their biopsy specimens. When demographic characteristics of the patients were considered, we found that the patients with endometrial adenocarcinoma and endometrial hyperplasia with atypia had potential risk factors for endometrial pathology such as chronic anovulation, diabetes or hypertension. This study confirms that routine endometrial sampling in asymptomatic postmenopausal women is not warranted, but patients with associated risk factors should be screened for endometrial pathology before starting estrogen replacement therapy.