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A case is reported about a 75-year-old man with a large abdominal lymph node metastasis caused by prostate cancer effectively treated by a high dose of diethylstilbestrol-diphosphate. The usefulness of diethylstilbestrol-diphosphate for prostate cancer patients with lymph node metastasis is emphasized.
Indenestrol A (IA), one of metabolites of the indanyl group of diethylstilbestrol, has a stronger binding affinity for the estrogen receptor and also a weaker uterotropic activity than endogenous estradiol. We tested the microbial mutagenicity of structural isomers of indenestrol A and indenestrol B (IB) in Salmonella typhimurium TA100 and TA98 and in Escherichia coli WP2 uvrA to investigate whether the interaction of diethylstilbestrol or IA with genomic DNA has any part in their carcinogenicity and other biological activities. In the absence of S9 mix, (+/-)-IA was cytotoxic at higher doses (1 and 10 mumol/plate), and both (+/-)-IA and (+/-)-IB were non-mutagenic at lower doses (0.1-100 nmol/plate). In the presence of S9 mix, (+/-)-IA was cytotoxic at higher doses (0.5 and 1 mumol/plate), and at the other doses, (+/-)-IA and (+/-)-IB did not show any distinct increase in revertants. Although (+/-)-IA and (+/-)-IB showed a slight increase in the revertants in strain TA100 by the preincubation method without S9 mix, these results were considered to be negative, because no reproducible dose-revertants relationship necessary for a chemical to be determined as mutagenic was obtained. The S9 fraction interacted with (+/-)-IA or (+/-)-IB enzymatically or non-enzymatically, and weakened its cytotoxicity, so that the toxic dose was higher in the presence of S9 mix than in its absence. Both the plate incorporation and preincubation methods were used with a wide range of concentrations of (+/-)-IA and (+/-)-IB in the present experiment. No clear positive mutagenic data were obtained. These results are the first reports on the mutation assays of (+/-)-IA and (+/-)-IB, and suggest that they were non-mutagenic towards the bacterial strains tested. The study revealed that the cytotoxic activity of (+/-)-IA and (+/-)-IB did not correlate with DNA interaction, but was the result of a direct effect on microtubule polymerization, although indenestrols are known to have strong binding affinities for estrogen receptors.
Endometriosis was found in 39% and in utero diethylstilbestrol (DES) exposure in 5% of 397 infertile women who had undergone laparoscopy and/or laparotomy among 750 consecutively evaluated infertile couples. Fifty percent of the DES-exposed infertile women also had endometriosis, similar to the 39% with endometriosis among non-DES-exposed women. Cervical stenosis was found in 25% of all DES-exposed patients and in 83% of those who had undergone cryocautery or conization. However, 40% did not have endometriosis. Thus, while the frequency of endometriosis and cervical stenosis is extremely high in infertile women exposed in utero to DES, a significant association beyond that found in non-DES-exposed patients could not be established. Some of the infertility may be associated with cervical stenosis alone.
Alterations in the metabolism of testosterone (T) and dihydrotestosterone (DHT) induced by diethylstilbestrol (DES) or medroxprogesterone acetate (MPA) could account for the beneficial therapeutic effect of these agents in prostatic carcinoma. To investigate this possibility we sutdied plasma kinetics of T and DHT in 17 elderly patients with prostatic carcinoma, before and after treatment with DES (1 or 5 mg/d) or MPA (10 or 30 mg/d) for 30 days. Metabolic clearance rates (MCR) were determined with the single injection technique and by use of two compartment model, plasma concentrations (PC) of T and DHT by radioimmunoassay, the per cent of T bound to plasma protein (T-binding) by charcoal adsorption of the unbound steroid. Production rate (PR) and PC of T were lower, PR and PC of DHT were higher in our patients than in normal men. With both DES regimens, PR, PC and MCR of either androgen declined; however, T was suppressed to a much greater extent than DHT. In either instance, the decrease may have been caused by direct suppression of testicular androgen synthesis and/or by decreased gonadotropin stimulation. Enhanced T-binding played an additional role in reducing the free testosterone index. High and low dose of DES were equally effective. The low dose regimen of MPA did not influence androgen metabolism. MPA in the higher dose suppressed PR and PC of T and DHT, possibly due to effects on testicular synthesis or by gonadotropin suppression as suggested for DES. In contrast to DES, MPA failed to cause profound changes in MCR of either androgen or in T-binding. When judged by its influence on the metabolism of T and DHT in prostatic carcinoma, MPA in higher doses is much less effective than either dose regimen of DES.
Antiethinylestradiol antibodies were demonstrated in several oral contraceptive users. The antibodies could be precipitated from serum immune complexes by 25% saturated ammonium sulfate. This test of serum precipitation was applied to a comparative study of 116 women on O.C and 65 men treated with diethylstilbestrol for a prostatic cancer. Controls without hormones were included in each group. The test was shown to discriminate among the estrogen users reactive and unreactive persons. 34% of women and 41% of men had high levels of precipitated immunoglobulins in 25% saturated ammonium sulphate. Study of the specificity of the Igs purified from the precipitates in reactive cases, showed that they were binding ethinylestradiol with an affinity constant consistent with an antigen antibody reaction. It is concluded that the oral ingestion of two different synthetic estrogen compounds may induce antiestrogen antibodies. The relation of these antibodies with the increased incidence of vascular thrombosis is considered.
This study was based on cases accessioned in the Registry of Clear Cell Adenocarcinoma of the Genital Tract in Young Females to ascertain the incidence of diethylstilbestrol (DES)-related cancers by age and year of birth. For accuracy in estimating the size of the reference population for the incidence rates, calculations were restricted to 127 white residents of the United States who were exposed prenatally to DES or other nonsteroidal synthetic estrogens. The disease is exceedingly rare prior to age 14 when the incidence rate begins to rise rapidly. The incidence peaks at age 19 (median 19.2 years) and then drops precipitately. Thus, DES-related clear cell adenocarcinoma is unusual in that nearly all cancers have been diagnosed in a narrow age range of 10 years (14 to 23 years). Women born in 1951 to 1953 have higher incidence rates than those born in the previous or subsequent three-year period. This suggests that the prevalence of pregnancy-related use of DES was at a peak in the early 1950's. The cumulative risk of this type of genital cancer, through age 24, for DES-exposed female subjects is estimated to be in the range of 0.14 to 1.4 per thousand. The wide limits are due to the fact that the number of young women exposed is not known precisly. The low risk of disease and the narrow age range of the cases, relative to the long latency period, suggest that DES is an incomplete carcinogen. Other factors, possibly related to puberty, may be involved in the causation of this disease.
Monozygotic, 17-year-old, female twins exposed to diethylstilbestrol (DES) in utero and discordant for cervicovaginal clear cell adenocarcinoma are reported. Benign teratologic changes were present in both. The twin with cancer was treated by extensive operation and postoperative irradiation. No tumor has appeared in either twin in the 4 years subsequent to therapy. Discordance for cervicovaginal clear cell adenocarcinoma in this situation suggests that factors other than embryonic exposure to DES, extrauterine in location and nongenetic in character, were operative in tumorigenesis. The twins were compared in regard to lifetime radiation exposure and evidence of previous viral disease. The only substantial difference was an elevated titer of antibody in the twin with cancer to the capsid antigen of the Epstein-Barr virus, a herpesvirus with oncogenic capability.
There was a marked regression of structural abnormalities associated with in utero exposure to diethylstilbestrol (DES) among 173 women observed for up to 5 years. Cervical ectopy, present in 121 women at initial examination, decreased in extent in 91 women (75.2%) and disappeared completely in 38 (31.4%). The cervicovaginal hood (CVH), present initially in 123 women, diminished in 65 patients (52.8%) and disappeared completely in 35 (28.4%). The longer the follow-up period, the greater the extent of resolution of these lesions. Patients with both findings at entry into the study showed parallel diminution of ectopy and CVH. The investigation documents that DES-associated ectopy and CVH are labile lesions which tend to decrease in extent with time and may eventually disappear.
Hysterosalpingography (HSG) was performed on 267 diethylstilbestrol (DES)-exposed women. One hundred eighty-five (69%) of these women demonstrated an abnormality and 82 women had normal findings. A relationship between abnormal x-ray findings and structural abnormalities of the cervix and vaginal epithelial changes was noted. Ninety-three women on whom roentgenography was performed had a total of 144 pregnancies. The pregnancy outcome in this group of women was significantly worse than that found in a control population of 87 women who had 147 pregnancies. In addition, women with abnormal x-ray films were found to have a poorer pregnancy outcome than the group of women with normal findings. The women with abnormal x-ray films had more ectopic pregnancies, spontaneous abortions, and premature deliveries than women with normal x-ray films although these differences were not statistically significant. Significantly fewer women with abnormal findings than women with normal x-rays were delivered of term infants.
The effect of diethylstilbestrol (DES) on the percent conversion of a 14C-progesterone (14C-P) substrate to 14C-testosterone (14C-T) when added to incubates fo rat testicular homogenates has been measured. Similarly the effect of DES administered parenterally to intact adult rats at 9 dose regimens on such conversion has been evaluated. In addition, in the latter group serum luteinizing hormone (LH) levels were assessed simultaneously. DES added in-vitro significantly reduced T formation at every level. Only the large parenteral dose of DES affected T synthesis after 24 hours, while every parenteral dose significantly reduced T synthesis with 4 and 8 day regimens. Mean serum LH levels failed to reflect a significant decrease at the 1 and 4 day dose level, but did decrease significantly in 2 of 3 groups on the 8 day regimen. These results suggest that there is a direct effect of DES at a testicular level inhibiting T synthesis not associated with a simultaneous drop in mean serum LH levels. A measurable decrease in LH concentration does occur with continued treatment.
Exposure to diethylstilbestrol (DES) in utero is associated with adverse effects on the reproductive tract in male and female progeny. These effects include epididymal cysts, microphallus, cryptorchidism, and testicular hypoplasia in male subjects and adenosis, clear cell adenocarcinoma, and structural defects of the cervix, vagina, uterus, and fallopian tubes in female subjects. As these offspring have reached reproductive age, reports of adverse reproductive performance have been published, including still controversial reports of menstrual dysfunction and infertility. More well established are increased rates of spontaneous abortion, ectopic pregnancy, premature deliveries, and perinatal deaths, all contributing to an increase in overall adverse pregnancy outcome. Often there is correlation between the DES-associated anatomic abnormalities in the reproductive tract and the adverse reproductive performance. Altered male reproductive capacity is also suggested by diminished semen analyses and sperm penetration assays. A detailed review of these effects of in utero DES exposure is presented.
Information on reproductive history, gynecologic operations, and examinations was analyzed for 338 diethylstilbestrol (DES)-exposed and 298 unexposed women whose mothers participated in an evaluation of DES use in pregnancy 28 years ago. A history of infrequent menses (less often than every 36 days) was reported more commonly by the exposed women (32%) than by the unexposed women (15%) and the mean duration of menstrual flow was also less. A greater number of exposed women than unexposed women experienced primary infertility (53 versus 19). The reasons for these differences are not currently known. Comparison of the outcomes of first pregnancies showed a higher proportion of premature births, spontaneous abortions, and ectopic pregnancies in the exposed women (P less than 0.001). The difference in the occurrence of ectopic pregnancies was statistically significant (8 versus 0; P less than 0.005). An adverse pregnancy outcome was more likely in DES-exposed women with cervicovaginal ridges. However, when the outcome of all pregnancies were considered, 81% of the exposed women had at least one living child. More exposed women than unexposed women had gynecologic surgical procedures, which may, in part, be due to the increased medical surveillance of the exposed group. The spectrum of diseases at operation in both groups was similar. Adnexal masses and pelvic inflammatory disease were more commonly reported among the exposed women while the occurrence of endometriosis in both groups was similar. For the exposed women who had been examined at the Chicago Lying-In Hospital over a 4-year period, epithelial changes in the vagina had disappeared in 32% and cervicovaginal ridges had disappeared in 57%.
The association between the use of diethylstilbestrol (DES) and vaginal and cervical adenocarcinoma and adenosis in the progeny was first reported by Herbst et al. in 1971. This progeny will reach a peak as far as reproduction is concerned in this decade. It is estimated that 2 million women may be involved to varying degrees. Changes in uterine and cervical contour and structure have been detailed. Thus DES exposure and anatomic changes in the Müllerian system have been documented. In this report 16 women in the reproductive age group who were exposed to DES in utero and presented with infertility are discussed. On workup for infertility they were found to have unique tubal morphologic features consisting of a foreshortened, convoluted tube with "withered" fimbria with a pinpoint os at laparoscopy. The diagnosis could not be made at the time of hysterosalpingogram. Three patients had surgery in an attempt to correct this condition; and in all cases the surgery was unsuccessful. No statistical data is offered as to epidemiologic factors or incidence rates, but the suspected increase in infertility and ectopic pregnancy rates in patients with DES exposure may corroborate these findings.
We compared the incidence of breast cancer in 3033 women who had taken diethylstilbestrol (DES) in pregnancy during the period from 1940 to 1960 with the incidence in a comparable group of unexposed parous women. We ascertained vital status in 95 per cent of the exposed women and in 93 per cent of the unexposed women and received completed questionnaires for 88 and 85 per cent, respectively. With over 85,000 woman-years of follow-up in each group, the incidence of breast cancer per 100,000 woman-years was 134 in the exposed group and 93 in the unexposed group, yielding a crude relative risk of 1.4 (95 per cent confidence interval, 1.1 to 1.9). The elevated incidence did not appear to be due to bias or to confounding by other risk factors measured in the study. Breast-cancer mortality was slightly higher in the exposed women (relative risk, 1.1) but not significantly so (95 per cent confidence interval, 0.7 to 2.0). We conclude that the incidence of breast cancer is moderately increased in women given DES, but we cannot exclude the possibility that some unrecognized concomitant of DES exposure accounts for this increase.
Diethylstilbestrol (DES) was widely prescribed to pregnant women from 1940 to 1960. This resulted in multiple benign abnormalities of the genital tract and occasional malignant transformation in women who had been exposed to DES in utero. Over 300 cases of clear cell adenocarcinoma of the vagina have been described to date. In this study, 18 DES-exposed women and 20 normal age-matched controls were studied with ultrasound. An estimated uterine volume of 49.4 cm3 +/- 25.5 SD was found in the exposed subjects, compared with 90 cm3 +/- 22 SD in the normal subjects. Three out of 18 women (16%) had a T-shaped uterus. Ultrasound can detect some of the uterine abnormalities which occur due to DES exposure.
Uterine anomalies were demonstrated by hysterosalpingography (HSG) in 4 of 5 diethylstilbestrol (DES) exposed young women with fertility disturbances. The anomalies included malformed uterine cavities and cervical incompetence. It is suggested that HSG in DES exposed women with fertility disturbances be performed early in the process of infertility investigation and cerclage should be considered when uterine anomalies are demonstrated. Tubal pregnancy should be ruled out by ultrasonography early during pregnancy in DES-exposed women.
Sequential examination and interview of diethylstilbestrol-exposed (DES-exposed) and -unexposed women verified that DES exposure has no effect on age at menarche and indicated no differences in the age at first coitus, pregnancy and live birth. Analysis of variance indicated that there is an age-related increase in oligomenorrhea in DES-exposed women as compared to unexposed women that disappears as the patients reach their late 20s. Prospective data collection is required to substantiate this finding. There appears to be no substantial effect of in utero exposure to DES on women's ability to conceive.
A case of a child with acute lymphoblastic leukemia (ALL) is reported. The child's mother was exposed to diethylstilbestrol (DES) in utero during the first two trimesters of pregnancy. Causal association for this child's leukemia could have resulted either from a maternal germ cell event or abnormal DES-induced intrauterine environment.