Harry K. Ziel

Increased Risk of Endometrial Carcinoma among Users of Conjugated Estrogens

The possibility that the use of conjugated estrogens increases the risk of endometrial carcinoma was investigated in patients and a twofold age-matched control series from the same population. Conjugated estrogens (principally sodium estrone sulfate) use was recorded for 57 per cent of 94 patients with endometrial carcinoma, and for 15 per cent of controls. The corresponding point estimate of the (instantaneous) risk ratio was 7.6 with a one-sided 95 per cent lower confidence limit of 4.7. The risk-ratio estimate increased with duration of exposure: from 5.6 for 1 to 4.9 years exposure to 13.9 for seven or more years. The estimated proportion of cases related to conjugated estrogens, the etiologic fraction, was 50 per cent with a one-sided 95 per cent lower confidence limit of 41 per cent. These data suggest that conjugated estrogens have an etiologic role in endometrial carcinoma.

Stroke in Users of Low-Dose Oral Contraceptives

BACKGROUND Previous studies have linked the use of oral contraceptive agents to an increased risk of stroke, but those studies have been limited to oral contraceptives containing more estrogen than is now generally used. METHODS In a population-based, case-control study, we identified fatal and nonfatal strokes in female members of the California Kaiser Permanente Medical Care Program and who were 15 through 44 years of age. Matched controls were randomly selected from female members who had not had strokes. Information about the use of oral contraceptives (essentially limited to low-estrogen preparations) was obtained in interviews. RESULTS A total of 408 confirmed strokes occurred in a total of 1.1 million women during 3.6 million woman-years of observation. The incidence of stroke was thus 11.3 per 100,000 woman-years. On the basis of data from 295 women with stroke who were interviewed and their controls, the odds ratio for ischemic stroke among current users of oral contraceptives, as compared with former users and women who had never used such drugs, was 1.18 (95 percent confidence interval, 0.54 to 2.59) after adjustment for other risk factors for stroke. The adjusted odds ratio for hemorrhagic stroke was 1.14 (95 percent confidence interval, 0.60 to 2.16). With respect to the risk of hemorrhagic stroke, there was a positive interaction between the current use of oral contraceptives and smoking (odds ratio for women with both these factors, 3.64; 95 percent confidence interval, 0.95 to 13.87). CONCLUSIONS Stroke is rare among women of childbearing age. Low-estrogen oral-contraceptive preparations do not appear to increase the risk of stroke.

Estrogen and endometrial carcinoma. An independent pathology review supporting original risk estimate.

Initial evidence suggested that estrogen therapy increases the risk of endometrial carcinoma. It was then suggested that some studies may have exaggerated the hazard of estrogen therapy by including patients with atypical endometrial hyperplasia among those having endometrial carcinoma. Three internationally recognized pathologists reviewed the histology slides available from the Ziel and Finkle study, which originally reported a risk ratio of 7.6 for estrogen users. At least one of the pathologists concurred with the original diagnosis in all but one case. Furthermore, all pathologists aggreed that 74 per cent (66/89) were correctly diagnosed. In the 66 patients with unanimous diagnosis, 61 per cent (40/66) had used conjugated estrogens, versus 57 per cent (54/94) in the original study. On the basis of 66 patients and 132 matched controls, the revised risk-ratio estimate is 8.1 (with a one-sided 95 per cent lower confidence limit of 4.5), validating the original estimate.

Myocardial infarction in users of low-dose oral contraceptives*

Objective To determine the relationship between the use of low-dose (less than 50 μg estrogen) oral contraceptives (OC) and myocardial infarction. Methods In this population-based case-control study, all incident myocardial infarctions in women, ages 15–44 years who were members of the Kaiser Permanente Medical Care Program, Northern and Southern California regions were ascertained during a 39-month period from 1991 through 1994. For each woman with myocardial infarction, up to three age- and facility-matched controls were chosen at random from female members. Information about OC use (predominantly low-dose preparations) was obtained in face-to-face interviews. Results There were 187 incident cases of myocardial infarction during 3.6 million woman-years of observation (incidence rate, 5.2 per 100,000 woman-years). The prevalence of several risk factors for myocardial infarction was lower in controls who were current users of OCs than in controls who were noncurrent (past and never) users. The odds ratio for myocardial infarction in current OC users compared with noncurrent users was 1.65 (95% confidence interval 0.45, 6.06) after adjustment for major risk factors and for race and ethnicity, corresponding to an excess risk of less than one case per 100,000 woman-years. The study had 80% power to detect a relative risk of 2.3 (one-sided test, α = .05). The odds ratio of myocardial infarction in past OC users was not elevated. Conclusion With respect to myocardial infarction, low-dose oral contraceptives can be used safely by women who lack risk factors for coronary heart disease.

Adenocarcinoma of the uterine cervix

Abstract The accepted current practice in the treatment of adenocarcinoma of the uterine cervix is radiation therapy. Opinion is frequently expressed in the literature that adenocarcinomas are not as easily controlled by irradiation as squamous cell carcinomas of the cervix. For this reason it has been the practice of some physicians to follow radiation therapy by conservative hysterectomy. The problem to be presented is whether adenocarcinoma of the cervix is to be treated with radiation therapy alone, or in combination with conservative hysterectomy. This paper deals with 30 patients with adenocarcinomas of the cervix treated primarily with radiation therapy and gives the survival rates for these patients. Our results indicate a 50 per cent 5 year survival for these patients treated primarily with radiation therapy. In the literature are reported series of patients treated with irradiation plus surgery, with 80 to 84 per cent 5 year survivals. Seven of our 30 patients died of local pelvic disease. If conservative hysterectomy had been done, and these 7 patients had survived, we project a 5 year survival rate of 80 per cent, matching the results reported in the literature for combined therapy. We believe that irradiation alone is not adequate for adenocarcinoma of the cervix. We recommend the addition of conservative hysterectomy if the goal is improval in survival rate.

Endometrial cancer risk after discontinuing use of unopposed conjugated estrogens (California, United States).

To examine the decline in risk of endometrial cancer after discontinuation of use of conjugated estrogens, we conducted a case-control study in a prepaid health plan. We identified 318 patients who had endometrial cancer but had no history of bilateral oophorectomy and had been in the Southern California (United States) Kaiser Foundation Health Plan for more than 10 years. For each patient, one or two control members were selected, 599 in all, matched for age and duration of membership at the time of cancer detection and who had had neither hysterectomy nor bilateral oophorectomy. A history of prescriptions for conjugated estrogens and of potential confounders was obtained for each subject by reviewing outpatient medical records. Rate ratios (RR) contrasting users with nonusers were estimated by time of latest prescription. We found that estrogen-induced risk of endometrial cancer decreases rapidly as the estrogen-free interval increases. The RR estimates, adjusted for duration of use and potential confounding factors, declined from 5.0 for those receiving their latest prescription within 24 months (95 percent confidence limits [CL]=2.6–9.8), to 1.8 for those receiving their latest prescription within 24 to 48 months (CL=0.9–3.7), to values near one for each latest prescription interval earlier than 48 months ago (P for trend = 0.0004). For those who used conjugated estrogens extensively (five or more prescriptions, five to 10 years ago), the RR estimate declined from 5.1 for those whose latest prescription was within two years to 0.6 yr for those whose latest prescription was four to five years previously (P for trend = 0.05).

Management of gestational diabetes

Abstract This review studies 100 pregnancies of gestational diabetic patients during the past 3 years. Seventy-seven per cent were delivered after the spontaneous onset of labor at term. The perinatal mortality rate was 1 per cent, comparing favorably with the general perinatal mortality rate for our hospital. The perinatal morbidity rate was 8 per cent; half of this morbidity caused by birth trauma secondary to macrosomia with difficult vaginal delivery. Excessive fetal size appeared to be strongly associated with a maternal history of macrosomia. This significant morbidity secondary to macrosomia suggests a more liberal use of cesarean section when the fetal weight is estimated to be greater than 9 lbs.

A guest editorial: dialog between basic and clinical science: relaxin as a possible cause of symphyseal separation.

Too often, the knowledge derived from basic science research fails to reach those caregivers who could use it to introduce timely new therapeutic options. Indeed, this lack of communication was discussed by the former editor of Obstetrics and Gynecology, S. Leon Israel (1906–1971), as long ago as April 1961 in the presidential address he gave at the 17th Annual Meeting of the American Society for the Study of Sterility. In that address (1), Dr. Israel emphasized the importance of communication between researchers in the basic and clinical sciences by referring to these aspects of science as “the yin and yang of science” (1). He pointed out that although these aspects of science seemed opposite, they were mutually complementary, and both were necessary to paint a total picture. With a somewhat trite analogy that graphically conveyed his point, Israel added that “...reproduction, the crowning expression of fertility, is accomplished by conjunction of two unlike organs.... We must continue to decry the separateness of two self-centered disciplines, laboratory research and clinical investigation.” (1 pp. 398, 401)

Stroke in Users of Low-dose Oral Contraceptives.

Carolei and Marini suggest that a response bias among controls and/or a failure to control for cardiac disease may account for the authors findings of a protective effect of oral contraceptives (OCs) against ischemic and hemorrhagic stroke. Hypertension one of the variables suggested as a source of response bias due to its association with both the risk of disease and of OC use is the only such variable for which complete medical record data are available for review. In this case the response rate was 77.0% among controls without hypertension and 77.4% among controls with hypertension. After adjustment for cardiac disease as well as the variables controlled in the original report the odds ratios among former OC users compared to never-users were 0.48 (95% confidence interval 0.23-0.97) for ischemic stroke and 0.91 (0.42-1.96) for hemorrhagic shock--ratios not substantially different from those reported in the paper. Although the authors reject claims of selection bias they note that the association of past OC use and reduced risk of stroke cannot be assumed to be causal until more studies detect a similar protective effect of OC use.