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This review of the connection between unopposed estrogen therapy for climacteric symptoms and the development of endometrial hyperplasia briefly outlines the history of the association, and then concentrates on clinical classification problems which muddy the attempts to come to a clear understanding of the relationship between estrogen replacement therapy (ERT) and endometrial cancer. Little agreement exists about the definition of endometrial pathology and of the malignant potentials of different types of hyperplasia. This paper classifies 4 types of hyperplasia: 1) cystic hyperplasia, which has the risk of malignant change of less than 2%; 2) adenomatous hyperplasia, which has a risk of malignant change from 12-25%; 3) atypical hyperplasia, which has a malignancy potential of 45%; and 4) carcinoma in situ, which is malignant. The following conditions are discussed as they are associated with endometrial hyperplasia and adenocarcinoma: 1) obesity; 2) anovulation; 3) late menopause; 4) Stein-Leventhal syndrome; 5) functioning ovarian tumors; and 6) diabetes history. In addition hypertension and cancers of the breast and ovary occur more often with endometrial cancer than would be expected by chance. The remainder of the paper discusses the administration of exogenous estrogens unopposed, exogenous progestins, and their concurrent use, especially in controlling menopausal symptoms. Prevention, diagnosis, and treatment of hyperplasia are discussed. In terms of prevention, a study showed that low-dose cyclical Premarin (.625 mg) resulted in an incidence of hyperplasia of 7% and with higher doses (1.25 mg) rose to 15%. The addition of d-norgestrel for 7 days to the high dose of Premarin reduced incidences to 3%, whereas estrogen plus low-dose norethindrone resulted in 0% incidence of cystic hyperplasia. It is recommended that the unopposed use of estrogens be avoided if possible, although short-term therapy up to 6 months is probably safe. Longer term therapy must have added progestogen, and endometrial sampling in the form of Vabra curettage should be performed every year in patients taking unopposed estrogens and every 3 years in patients taking combined estrogen therapy.
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PMID:Oestrogens and endometrial hyperplasia. 699 95

A review of literature, mainly the results of studies conducted in America, shows obesity, diabetes mellitus, hypertension, infertility/nulliparity, late menopause, high endogenous oestrogen production, and the use of oestrogens to be the main factors associated with the development of endometrial carcinoma. Whilst most of these factors undoubtedly apply irrespective of country, doubt in Finland about the use of oestrogens being a risk factor was one of the reasons prompting the study reported here. This study, which was conducted in Turku, Finland, involved 318 endometrial carcinoma patients, 282 of whom could be paired with controls matched for age, height and weight, and social class. The data show the use of oestrogens per se not to be a risk factor. The fact that there appears to be a risk in America, where most of the oestrogenic preparations used are based on conjugated equine oestrogens, but not in Finland, where the preference is for preparations based on oestriol and oestradiol and where conjugated oestrogen preparations are relatively rarely used, supports the hypothesis that the risk depends on the type of oestrogen used.
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PMID:Endometrial carcinoma risk factors, with special reference to the use of oestrogens. 699 4

The epidemiology of cancer of the endometrium is summarized. The findings are reported, and emphasis is on preventive approaches to cancer of the endometrium, particularly as to the role that physicians as well as women themselves can play. Attention is directed to incidence patterns, geographic distribution, age, race, time trends, survival rates, histopathologic consideration, and etiologic considerations (hormonal factors, obesity, diabetes mellitus, hypertension, and familial disposition). Recent reports indicate an increase in endometrial carcinoma, while the incidence of cervical carcinoma has substantially decreased. Endometrial cancer is usually a disease associated with postmenopausal women, mostly in the 6th and 7th decades, although rare cases have been reported in women under age 20 and over age 90. It is estimated that in 1981 there will be 38,000 newly diagnosed carcinomas of the endometrium and 3200 deaths due to endometrial carcinoma. There is little reliably comparable information available on endometrial cancer in different regions of the world. The incidence rate for endometrial cancer for U.S. white women is nearly double that for black women. For almost 4 decades before 1970 the incidence of cancer of the corpus uteri remained relatively stable. In a study conducted by Weiss et al. it was shown that the incidence of endometrial cancer increased by 34-75% between 1969 and 1973 in spite of a presumed increase in the rate of hysterectomy, which means a decreased population at risk during this same period. It is clear that obesity is a key risk factor for endometrial cancer, particularly as this obesity appears to be related to a high fat diet and consequently to higher levels of plasma urinary estrogens. It also appears that patients with heightened estrogenic stimulation reflected by a late menopause and heavy menstrual flow are at greater than average risk for endometrial cancer. As far as postmenopausal hormonal replacement therapy is concerned, the evidence appears strong that their use does increase the risk of endometrial cancer, particularly if such therapy is given for a long period of time and at relatively high doses. Possibly the ideal solution may be to give, when indicated, hormone replacement therapy at the least possible estrogen dose and together with progesterone, and to take the medication in cycles rather than on a constant basis.
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PMID:Epidemiology of cancer of the endometrium. 703 6

The present level of understanding of the known risks of oral contraceptive (OC) use are summarized. The findings of many investigations in the late 1960s and early 1970s may no longer be totally appropriate because OCs available then had higher dosages than today. Also, early studies enrolled predominantly women in their 20s, who are now almost all more than 35 years old. Thus, the risks observed in these studies may not be applicable to younger women using OCs today. Another consideration has been underscored by the results of the Walnut Creek Study. Behavioral characteristics such as smoking, drinking, and sexual activity are factors which can strongly confound risks of OC use and must be considered when assessing current and future investigations. Many studies have clearly shown that the most serious life threatening danger associated with OC use is that of cardiovascular complications arising from the interaction of OC use and smoking. The increased risks attributable to smoking while using OCs account for a substantial number of the deaths recorded. The Walnut Creek Study showed a somewhat different outcome. Its data suggest no significant risk of myocardial infarction (MI), ischemic heart disease, cerebral thrombosis, or ischemic cerebrovascular disease associated with OC use, but there were nonsignificant increases noted in some cardiovascular diseases which appeared to be explained by a synergism between current use and heavy smoking. Age also has a strong influence on risk for cardiovascular disease. The results of earlier studies seem to indicate that OC use is associated with a risk of subarachnoid hemorrhage. The Walnut Creek Study also noted an increased risk of subarachnoid hemorrhage associated with OC use and found that risk increased with use. Several studies have shown that the incidence of venous thrombosis seems dependent on the dosage of the OC used. An overwhelming majority of studies on the carcinogenicity of OCs have found no increased incidence of cancer of the ovaries, uterus, or breast among users. In regard to both ovaries and endometrium, there is some evidence that OCs may be protective. Several studies have concluded that OC users have a slightly increased risk of developing malignant melanoma. The results of the Oxford/Family Planning Study show that although previous use of OC by nulliparous women may delay future childbearing by several months, it does not impair longterm potential for pregnancy. No increase in risk of clinically apparent diabetes mellitus has been reported in users. In addition to their possible protection against ovarian and endometrial cancer, OCs may reduce the risk of at least 5 other diseases: benign breast disease; deficiency anemia; arthritis, pelvic inflammatory disease; and ovarian cysts.
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PMID:The pill: an evaluation of recent studies. 704 36

A case-control study of the epidemiology of endometrial cancer in women aged 45-74 years was carried out in 7 hospitals in Connecticut from 1977-79. 167 cases of adenocarcinoma, adenocanthoma, and adenosquamous neoplasms of the endometrium were included. 903 women of the same age admitted to surgical services except gynecology served as controls. Response rates were 67% for cases and 72% for controls. Odds ratios for the association between selected variables and endometrial cancer, adjusted by linear logistic regression for the effect of all other variables in the table, indicated that elevated risks were associated with being white and being well-educated, among demographic variables, and with nulliparity, fewer pregnancies, later age at menopause, use of estrogen replacement therapy, and a history of ovarian or endometrial cancer in mother or a sister, among reproductive variables. The longer estrogen replacement therapy was used, the higher the risk, up to 10 years of use. Heavier women were found to be at higher risk, although the risk for women of medium weight was only slightly increased. Women who reported a history of diabetes had a somewhat increased risk, while a history of ever having blood clots in the veins or of having had tubes tied was associated with reduced risk. Use of oral contraceptives was associated with a decreased risk, although the decrease did not reach statistical significance.
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PMID:A case-control study of cancer of the endometrium. 711 42

The study included 191 patients with obesity, atherosclerosis, diabetes mellitus, endometrial cancer, breast cancer and healthy subjects of various age. Somatomedin activity was determined by incorporation of radioactive natrium sulfate in vitro into the cartilage of female rats. The results of the study showed that somatomedin activity was not changed in subjects with normal metabolic parameters and ranged from 0.47 to 0.69 U/ml. In patients with diabetes mellitus, atherosclerosis and obesity accompanied by increased blood concentration of cholesterol and triglycerides, somatomedin activity rose up to 1.36- 1.62 U/ml. In patients with breast and endometrial cancer somatomedin activity was also increased, particularly in those with hypercholesterolemia and hypertriglyceridemia (3.04 U/ml for breast cancer patients and 2.20 U/ml for endometrial cancer patients). Theoretically, this may promote proliferation of somatic cells and thus contribute to tumor processes in oncological patients whose pool of cells is extremely sensitive to mitogenic agents.
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PMID:Interrelation between lipidemia and somatomedin activity in cancer and age-associated pathology. 713 38

During the 20 years since the oral contraceptive was introduced, it has been used by some 150 million women around the world, and is perhaps the most carefully monitored medication in history. This vast body of research shows that for the overwhelming majority of healthy women under 30, the benefits of the pill continue to outweigh the risks. The most serious life threatening risks are those involving the cardiovascular system: heart attack, stroke, and throboembolism. However, deaths from these causes would be reduced by 1/2 if women using the pill did not smoke; further reductions would result if women with high blood pressure, high chloresterol levels and diabetes millitus did not use the pill. There is no evidence thus far to justify fears that the pill might be associated with an increased risk of cancer. Most studies show that not only is there no association between pill use and cancer of the ovaries, uterus and breast, but pill use may protect against ovarian and endometrial cancer. Women taking the pill are 1/4 as likely to develop benign breast lumps as nonusers, 1/14 as likely to develop ovarian cysts, 2/3 as likely to develop iron deficiency anemia, and 1/2 as likely to develop rheumatoid arthritis -- all relatively common conditions. In addition, pelvic inflammatory disease, a major cause of infertility, appears to occur only 1/2 as often among pill users as among nonusers. The risk to life among pill users younger than 30 who do not smoke is very small (virtually the same as that of users of the IUD, diaphragm, or condom) and is much lower than the risk of birth-related deaths among women who use no birth control.
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PMID:The pill at 20: an assessment. 720 90

Cancer prevention as related to the problem of cervical and endometrial cancer involves a great number of factors that are considered contributory to the development of neoplasms in the uterus. Lifestyles encouraging the development of cervical cancer are different from those encouraging endometrial cancer. Cancer of the cervix is a disease of the inner city. It is seen in those staring intercourse in their teens, having multiple partners, having many children, and coming from the low socioeconomic groups. Semen and herpes virus II may have an adverse effect on immature cells, but there are no hard data to confirm these roles. Cancer of the endometrium is a disease of suburbia. The American Cancer Society estimates that there will be 38,000 new cases of endometrial carcinoma in 1980, making it the most common female genital cancer. Women at highest risk for later carcinoma of the endometrium are those who have obesity, diabetes, infertility, irregular menses and failure of ovulation, adenomatous hyperplasia, and/or prolonged estrogen administration. For both cervical and endometrial cancers, it is possible to identify the high-risk patient, to detect changes at an early stage, and, by instituting appropriate therapy, to prevent a more serious problem. It is obvious that prevention, detection, and treatment are all closely intertwined. This paper identifies the patient at high risk and makes suggestions for correcting any imbalance that may predipose to the development of invasive cancer.
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PMID:Uterine cancer (prevention). 723 68

The outpatient monitoring of the endometrium is mandatory in a defined high-risk population. Countless reports support this thesis. The authors' candidates for screening include initial samples of all patients over 40 years of age, with annual evaluation of a high risk group. This included patients with a family history of endometrial cancer, where the endometrium is subjected to continue estrogen stimulation either exogenous or endogenous, abnormal perimenopausal or postmenopausal bleeding, low fertility, and the medical triad of obesity, diabetes and/or hypertension. The methodology of monitoring is outlined and assessed. The ease of performance, inexpensiveness, and accuracy of 94% had led the authors to support cytology. Combined cytology, histology and hysteroscopy are needed in selected cases.
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PMID:Endometrial monitoring of high-risk women. 727 75

Clinical and pathologic findings were compared in 43 postmenopausal endometrial carcinoma patients who had received exogenous estrogens prior to diagnosis and 79 similar patients unexposed to estrogens. Estrogen non-users were more likely to manifest lower parity, later menopause, obesity, hypertension, and diabetes, all of which have been considered to be constitutional risk factors for the development of endometrial carcinoma. Although estrogen users and non-users had similar extent of disease as judged by clinical stage, there was a tendency to more myometrial invasion in hysterectomy specimens from non-users, as well as greater frequency of unfavorable histologic types and grades of tumor. At short-term follow-up, more recurrences occurred in non-users, and this tendency appeared to be independent of clinical stage, histologic type, histologic grade, or modality of treatment. The significance of these and other observation to the determination of the risk-benefit ratio for estrogen administration is discussed.
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PMID:Endometrial carcinoma: clinical-pathologic comparison of cases in postmenopausal women receiving and not receiving exogenous estrogens. 738 46


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