Primary infertility in women exposed to diethylstilboestrol in utero

In a selected group of 40 women who had been exposed to diethylstilboestrol in utero, 18 conceived without difficulty and 22 had primary infertility. Among those with primary infertility there was a significantly higher rate of anatomical structural defects and a greater tendency for menstrual disorders than in those without infertility. Thirteen (59%) of the women with primary infertility conceived, most after treatment with ovulation stimulating drugs. Spontaneous abortion and tubal pregnancy were frequent (47% and 10% respectively) and similar in both fertility groups. Of 13 infertile women examined, 4 (31%) had mild hyperprolactinemia--a hithero unreported finding for such women.     

Primary infertility in women exposed to diethylstilboestrol in utero

Summary. In a selected group of 40 women who had been exposed to diethylstilboestrol in utero , 18 conceived without difficulty and 22 had primary infertility. Among those with primary infertility there was a significantly higher rate of anatomical structural defects and a greater tendency for menstrual disorders than in those without infertility. Thirteen (59%) of the women with primary infertility conceived, most after treatment with ovulation stimulating drugs. Spontaneous abortion and tuba1 pregnancy were frequent (47% and 10% respectively) and similar in both fertility groups. Of 13 infertile women examined, 4 (31%) had mild hyperprolactinemia—a hithero unreported finding for such women.     

Intractable primary infertility in women exposed to diethylstilbestrol in utero

Fertility factors were examined in 50 women with primary infertility and presumed in utero diethylstilbestrol (DES) exposure and in 50 age-matched controls. Uterine deformities and endometriosis were more frequent in the DES-exposed women than the controls. When managed from one to four years, only 4% of DES-exposed women with primary infertility conceived (with no conceptions resulting in a viable fetus) as compared to 44% of controls. Primary infertility of one to two years' duration with uterine deformities characteristic of DES exposure seems to signal a poor prognosis for pregnancy despite treatment of identifiable fertility factors.     

Benign cervicovaginal deformities in young women not exposed to diethylstilboestrol

During a 2-year period six women have been identified with benign cervicovaginal deformities of the type normally associated with diethylstilboestrol (DES) exposure in utero. In none of them could such a hormonal history be identified. It is suggested, in view of these findings, that benign cervicovaginal deformities are not unique to women exposed to DES in utero and some possible reasons why they have never previously been reported are presented.     

Infertility in women exposed to diethylstilbestrol in utero

To evaluate the reproductive consequences of prenatal diethylstilbestrol (DES) exposure, 33 infertile couples were studied in whom the female had been exposed to DES in utero. Infertility was attributed to uterotubal junction obstruction in 3 couples, anovulation in 7, endometriosis in 11, cervical obstruction in 2, adnexal adhesions in 2, oligospermia in 1 and luteal insufficiency in 3; in 4 couples no cause of infertility could be identified. No unique intraabdominal abnormalities attributable to DES exposure were observed. Four tubal pregnancies occurred in women with grossly normal oviducts. Nine of 11 women who had previously undergone surgical manipulation of the cervix (cryosurgery, cautery or conization) developed cervical stenosis, and 8 of them were found to have endometriosis. Despite our not having an appropriate referral infertility population for comparison, these findings are consistent with the following hypotheses regarding women prenatally exposed to DES: (1) surgical manipulation of the cervix more frequently leads to cervical stenosis and ultimately pelvic endometriosis, (2) tubal pregnancies may occur by a mechanism unrelated to salpingitis, and (3) the spectrum of problems causing infertility is similar to that in the non-DES-exposed population.     

Preeclampsia risk in women exposed in utero to diethylstilbestrol

OBJECTIVE: To assess whether preeclampsia risk is elevated in pregnancies of diethylstilbestrol (DES)-exposed daughters. METHODS: This study used data from the National Cancer Institute DES Combined Cohorts Follow-up Study. A total of 285 preeclampsia cases (210 exposed and 75 unexposed) occurred in 7,313 live births (4,759 DES exposed and 2,554 unexposed). Poisson regression analysis estimated relative risks and 95% confidence intervals (CI) for preeclampsia adjusted for age at the index pregnancy, parity, education, smoking, body mass index, year of diagnosis, and cohort. RESULTS: In utero DES exposure was associated with nearly a 50% elevation in preeclampsia risk. Adjustment for preeclampsia risk factors attenuated the relative risk slightly (1.42, 95% CI 1.04-1.94). The excess risk with DES was concentrated among women who developed preeclampsia in their first pregnancies (relative risk 1.81, 95% CI 1.17-2.79), who were exposed before 15 weeks of gestation (relative risk 1.57, 95% CI 1.11-2.23), and who were treated with magnesium sulfate (relative risk 2.10, 95% CI 0.82-5.42). Among DES-exposed women who had a prior hysterosalpingogram, preeclampsia prevalence was higher in those with uterine abnormalities (12.4%) than in those without (7.7%). CONCLUSION: These data suggest that in utero exposure to DES is associated with a slightly elevated risk of preeclampsia, and that one possible biological mechanism involves uterine abnormalities.     

Alterations in immune responsiveness in women exposed to diethylstilbestrol in utero

In order to study the effect of in utero diethylstilbestrol (DES) exposure on the immune system of adult women, the blastogenic response of peripheral blood lymphocytes to two mitogens was compared in eight DES-exposed patients and in eight age-matched controls with normal menstrual cycles and proven fertility. As measured by the uptake of 3H-thymidine (mean [+/- standard error]), response to the T-cell mitogen phytohemagglutin (PHA) was significantly higher (P less than 0.002) in cells of DES-exposed women (88.6 +/- 5.7 X 10(3) cpm) than in controls (44.0 +/- 8.9 X 10(3) cpm) at the lowest dose of mitogen tested (0.125 microgram/ml). Moreover, lymphocytes of DES-exposed subjects showed maximal blastogenic response to PHA at a concentration (0.125 microgram/ml) two to four times lower (P less than 0.002) than controls (0.25 microgram/ml to 0.5 microgram/ml). Cells of both DES-exposed subjects and controls were maximally responsive to pokeweed mitogen (PWM) at the lowest dose tested (0.625 microgram/ml). These findings suggest that in utero DES exposure is associated with a hyper-reactive immune response during the reproductive years.     

Altered immune response in adult women exposed to diethylstilbestrol in utero

OBJECTIVE: Between 1940 and 1970, 1.5 million female fetuses were exposed to diethylstilbestrol in utero. Numerous deleterious effects on reproductive anatomic and physiologic characteristics have been documented in these women. However, the effects of this exposure on nonreproductive systems, which may have lifelong consequences as this cohort of women progresses beyond the childbearing years, have received little attention. On the basis of an earlier preliminary observation of altered immune reponse, we hypothesized that diethylstilbestrol-exposed women may show abnormalities in T-cell-mediated immune response. STUDY DESIGN: Thirteen women exposed to diethylstilbestrol in utero were compared with 13 age- and menstrual cycle phase-matched control subjects with respect to the in vitro T-cell response to the mitogens phytohemagglutinin, concanavalin A, and interleukin 2. RESULTS: As compared with controls, tritiated thymidine incorporation by T cells harvested from diethylstilbestrol-exposed women was increased 3-fold over a range of concentrations in response to concanavalin A (P <.001), increased by 50% over a range of concentrations in response to phytohemagglutinin (P <.001), and increased 2-fold in response to the endogenous mitogen interleukin 2 (P <.05). CONCLUSIONS: In vitro evidence suggests that women exposed to diethylstilbestrol have alterations in T-cell-mediated immunity. These changes require further attention with regard to their characterization, their role in the pathogenesis of cancer and autoimmunity, and their presence in normal women exposed to diethylstilbestrol in utero.     

Findings in female offspring of women exposed in utero to diethylstilbestrol

OBJECTIVE: To examine a group of women (third-generation daughters) whose mothers were exposed in utero to diethylstilbestrol (DES) and compare their findings on pelvic examination with those noted in their mothers. METHODS: Letters were mailed to women documented to have been exposed in utero to DES who had given birth to a female offspring, inviting them to have their daughters come in for a detailed history and pelvic examination. Records of the mothers whose daughters appeared for examination were reviewed, and findings noted at the time of their initial examination were recorded. Detailed pelvic examination of the third-generation daughters included colposcopic examination and iodine staining of the vagina and cervix and Papanicolaou smear. The findings observed in these women were compared with those noted in their mothers at the time of their mothers' first examination. RESULTS: Twenty-eight third-generation daughters were examined. Three of the daughters were delivered from one mother. Review of the mothers' records indicated that 16 (61.5%) of the mothers exposed to DES during their pregnancy demonstrated structural changes of the cervix, upper vagina, or vaginal epithelial changes consisting of adenosis, nonstaining vaginal epithelium after application of iodine solution, or white epithelium within the vagina. None of the daughters were found to have changes usually associated with DES exposure. CONCLUSION: The absence of abnormalities in the lower genital tract in third-generation women compared with the high frequency of these abnormalities in their mothers suggests that third-generation carryover effects of in utero DES exposure are unlikely.     

Menstrual history of young women exposed in utero to diethylstilbestrol.

The menstrual histories of 218 patients exposed in utero to diethylstilbestrol (DES) were compared with those of 158 control subjects. No significant differences were revealed in the complaint of menstrual irregularities at either the initial or follow-up examination. Age at menarche was the same in both groups, and was the same as found in the United States as a whole. These findings differ from the report of a controlled trial in Chicago which suggests that there is a specific pattern of oligomenorrhea associated with DES exposure.     

Menstrual history and fecundity of women exposed and unexposed in utero to diethylstilbestrol

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.     

Human papillomavirus associated with vaginal intraepithelial neoplasia in women exposed to diethylstilbestrol in utero

Five out of 959 young women, exposed to diethylstilbestrol (DES) in utero, developed vaginal intraepithelial neoplasia while they were under follow-up in the Diethylstilbestrol-Adenosis Project at Baylor College of Medicine, Houston, Texas. We suggest that the development of the vaginal intraepithelial neoplasia at a younger age than usual may be caused by a higher susceptibility of the DES-exposed patient to factors associated with the development of intraepithelial neoplasia. A common finding in all five women was the detection of the deoxyribonucleic acid (DNA) of human papillomavirus types 6 or 16 in their lesions, using high-stringency in situ hybridization. The role of human papillomavirus and herpes simplex virus in the etiology of intraepithelial neoplasia is discussed. Close follow-up is recommended for DES-exposed patients, especially those who have risk factors known to be associated with genital neoplasia.     

One-year follow-up of infants exposed to ultrasound in utero

Neonatal and infant follow-up data from the Amniocentesis Registry of the National Institute of Child Health and Human Development were analyzed for possible effects of diagnostic ultrasound exposure in the second trimester of pregnancy. A total of 297 infants of mothers receiving both amniocentesis and diagnostic ultrasound were compared with a similar group of 661 infants of mothers who had amniocentesis but not ultrasound and with 949 infants exposed to neither amniocentesis nor ultrasound. Results of newborn and 1 year examinations were similar for the amniocentesis with ultrasound group when compared to the other two groups. However, in view of the small sample size and other limitations of these data, larger and more detailed studies are needed to adequately assess possible effects of ultrasound in pregnancy.     

Evaluation of seven- to nine-year-old children exposed to ritodrine in utero

Twenty children who had been exposed to ritodrine in the management of preterm labor between 24 and 34 weeks' gestational age were examined at seven to nine years of life and compared with matched control subjects. No significant differences were detected in factors of growth, neurologic findings, and psychometric testing.     

Detection of chromosomal aberrations by fluorescence in situ hybridization in cervicovaginal biopsies from women exposed to diethylstilbestrol in utero

Epidemiologic studies have associated estrogens with human neoplasms such as those in the endometrium, cervix, vagina, breast, and liver. Perinatal exposure to natural (17beta-estradiol [17beta-E(2)]) and synthetic (diethylstilbestrol [DES]) estrogens induces neoplastic changes in humans and rodents. Previous studies demonstrated that neonatal 17beta-E(2) treatment of mice results in increased nuclear DNA content of cervicovaginal epithelium that precedes histologically evident neoplasia. In order to determine whether this effect was associated with chromosomal changes in humans, the frequencies of trisomy of chromosomes 1, 7, 11, and 17 were evaluated by the fluorescence in situ hybridization (FISH) technique in cervicovaginal tissue from 19 DES-exposed and 19 control women. The trisomic frequencies were significantly elevated in 4 of the 19 (21%) DES-exposed patients. One patient presented with trisomy of chromosomes 1, 7, and 11, while trisomy of chromosome 7 was observed in one patient. There were two patients with trisomy of chromosome 1. Trisomy of chromosomes 1, 7, 11, and 17 was not observed in the cervicovaginal tissue taken from control patients. These data suggest that DES-induced chromosomal trisomy may be an early event in the development of cervicovaginal neoplasia in humans.