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American Journal of Epidemiology Advance Access originally published online on August 3, 2006
American Journal of Epidemiology 2006 164(7):682-688; doi:10.1093/aje/kwj257
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

Original Contribution

Age at Natural Menopause in Women Exposed to Diethylstilbestrol in Utero

Elizabeth E. Hatch1, Rebecca Troisi2, Lauren A. Wise3, Marianne Hyer4, Julie R. Palmer3, Linda Titus-Ernstoff5, William Strohsnitter6, Raymond Kaufman7, Ervin Adam7, Kenneth L. Noller6, Arthur L. Herbst8, Stanley Robboy9,10, Patricia Hartge2 and Robert N. Hoover2

1 Department of Epidemiology, Boston University School of Public Health, Boston, MA
2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
3 Slone Epidemiology Center, Boston University, Boston, MA
4 Information Management Services, Rockville, MD
5 Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, NH
6 Department of Obstetrics and Gynecology, New England Medical Center, Boston, MA
7 Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX
8 Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
9 Department of Pathology, Duke University Medical Center, Durham, NC
10 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC

Correspondence to Dr. Elizabeth E. Hatch, Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, Boston, MA 10029 (e-mail: eehatch{at}bu.edu).

Received for publication January 12, 2006. Accepted for publication March 22, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Age at natural menopause is related to several health outcomes, including cardiovascular disease and overall mortality. Age at menopause may be influenced by the number of follicles formed during gestation, suggesting that prenatal factors could influence menopausal age. Diethylstilbestrol (DES), a nonsteroidal estrogen widely prescribed during the 1950s and 1960s, is related to reproductive tract abnormalities, infertility, and vaginal cancer in prenatally exposed daughters but has not been studied in relation to age at menopause. The authors used survival analyses to estimate the risk of natural menopause in 4,210 DES-exposed versus 1,829 unexposed US women based on responses to questionnaires mailed in 1994, 1997, and 2001. DES-exposed women were 50% more likely to experience natural menopause at any given age (hazard ratio = 1.49, 95% confidence interval: 1.28, 1.74). Among women for whom dose information was complete, there were dose-response effects, with a greater than twofold risk for those exposed to >10,000 mg. The causal mechanism for earlier menopause may be related to a smaller follicle pool, more rapid follicle depletion, or changes in hormone synthesis and metabolism in DES-exposed daughters. Age at menopause has been related, albeit inconsistently, to several exposures, but, to the authors' knowledge, this is the first study to suggest that a prenatal exposure may influence reproductive lifespan.

diethylstilbestrol; longitudinal studies; menopause; prenatal exposure delayed effects; survival analysis

Abbreviations: DES, diethylstilbestrol; DESAD, Diethylstilbestrol Adenosis Project; HRT, hormone replacement therapy; NCI, National Cancer Institute


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Age at menopause is an important indicator of a woman's health status. Younger age at natural menopause has been linked with several health outcomes, including cardiovascular disease (1Go), osteoporosis (2Go), and overall mortality (3Go, 4Go), while late menopause carries a higher risk of breast (5Go) and endometrial (6Go) cancer. Cigarette smoking, especially current smoking, has been consistently linked with earlier age at menopause (7Go). Other factors related, with varying consistency, to age at menopause include parity, socioeconomic status, body mass index, oral contraceptives, and age at menarche (7Go–10Go). The timing of menopause is thought to be at least partially determined by the size of the original pool of ovarian follicles at birth and thus may plausibly be related to in utero exposures (11Go). Although health effects of exposure to diethylstilbestrol (DES) have been studied extensively, the question of whether DES exposure in utero might affect the timing of a woman's age at menopause has not been evaluated to our knowledge. One small study found no evidence for premature ovarian failure in DES-exposed women (12Go).

In addition to the well-known increased risk of clear cell adenocarcinoma of the vagina and cervix (13Go), women exposed to DES in utero have impaired fertility (14Go) and increased risks of miscarriage, ectopic pregnancy, and premature births (15Go). Most of these studies suggest that the mechanism for reduced fertility is related to teratogenic structural changes in the reproductive tract, such as a T-shaped uterus, cervical collars and hoods, and malformations of the fallopian tubes, rather than hormonal imbalances. However, some studies have reported changes in menstrual cycle patterns in DES-exposed women (16Go) and in levels of hormones, such as testosterone and prolactin (17Go, 18Go). These changes may also be related to fertility, and ultimately to age at menopause, in DES-exposed daughters. Animal studies have found reduced numbers of ova following in utero exposure to DES, which suggests a possible mechanism for earlier menopause in the DES exposed (19Go).

This study evaluated the relation between prenatal DES exposure and timing of menopause in a cohort of 4,210 exposed and 1,829 unexposed US women who have been part of the National Cancer Institute's (NCI) DES Follow-up Study.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study subjects
The NCI DES Follow-up Study began in 1992 and consists of four individual cohorts of DES-exposed and unexposed women, all with medical record documentation of exposure status. The study methods have been described in detail previously (20Go). Briefly, participants from three cohorts—Diethylstilbestrol Adenosis Project (DESAD), Dieckmann, and Horne—initially identified and studied during the 1970s, were traced and contacted for follow-up by NCI. Studies of the DESAD and Horne cohorts were observational, whereas the Dieckmann cohort originated from a clinical trial conducted in the 1950s to test whether DES was effective in preventing miscarriage and premature birth among women presenting for routine prenatal care at the University of Chicago (Illinois) (21Go). The bulk of the NCI study participants are from the DESAD cohort. A fourth cohort was identified through the Women's Health Study, originally conducted during the 1970s and 1980s to determine whether women exposed to DES during pregnancy had a higher risk of breast cancer (22Go). In 1992, DES-exposed mothers and a comparison group of unexposed mothers were asked for permission to contact their offspring, who were then recruited into the NCI combined cohort study.

Follow-up
Study subjects were contacted by mail and received a questionnaire in 1994, 1997, and 2001. At each follow-up, the women were mailed as many as two questionnaires, followed by a telephone interview with remaining nonrespondents. In addition to questions on cancer and other medical history, reproductive history, and a variety of risk factors, the questionnaires inquired about the occurrence of menopause. The 1994 baseline questionnaire asked, "Have your menstrual periods stopped; that is, have you been through menopause?" with four response categories: yes, periods stopped; had menopause but now have periods due to hormone therapy; no, still menstruating; not sure. Participants were also asked the age at which their periods stopped, the reason their periods stopped, and dates of hysterectomy and oophorectomy (including both unilateral and bilateral). The 1997 and 2001 questionnaires collected updated information on the occurrence and reason for menopause, date of the last menstrual period, use of hormone replacement therapy (HRT), and hysterectomy and oophorectomy.

A total of 7,439 women from the four cohorts were identified in 1992 as potentially eligible for follow-up. Of these women, 84 were deceased, and 804 had refused further contact during the original cohort studies or were untraceable. The mean age at last follow-up of women who did not participate in any of the NCI surveys was 30 years for both the exposed and unexposed. In 1994, of 6,551 women who were mailed questionnaires (88 percent of the original surviving cohort members), 5,707 responded (response rate of 87 percent). Response rates for the 1997 and 2001 surveys were 91 percent and 93 percent, respectively. As of 2001, 90 percent of both exposed and unexposed women who had ever participated in follow-up by NCI since 1994 were still being actively followed.

Approvals for the study were obtained from the human investigations committees at the five field centers and the NCI. Subjects indicated their informed consent by filling out and returning questionnaires or taking part in a telephone interview.

Data analysis
Women were considered naturally postmenopausal if they had not had a menstrual period in the past 12 months, had not experienced surgical menopause, and were not pregnant or breastfeeding. Women who began HRT (including birth control pills for menopausal symptoms) before the occurrence of menopause were treated as if they were premenopausal and were censored at the age of first use of HRT because of presumed effects on menstrual cycling that might result in misclassification of true age at menopause. Women who reported a hysterectomy or bilateral oophorectomy before the occurrence of natural menopause were censored at the age at which the surgery was performed. Women who were still menstruating, or had had a period within the last 12 months, were censored at their age at the last period. Women who were lost to-follow-up were also censored at their age at the last period. The age at which their last period occurred was used to estimate age at menopause for naturally menopausal women. Women who reported natural menopause on the 1994 questionnaire were asked how old they were at their last period. In the 1997 and 2001 questionnaires, women were asked for the date of their last menstrual period; for these women, exact age at menopause was calculated by subtracting the date of birth from the date of their final menstrual period.

Information on potential confounding variables was collected in each of the three questionnaires, and some information was also available from data collected during the original studies conducted during the 1970s. Data on birth weight came from a variety of sources, including the original medical record or interviews with the mother or daughter at the time of enrollment in the original study. Age at menarche was collected during the original cohort studies in the 1970s, except for women from the Women's Health Study cohort, who were first enrolled in 1994. Data on marital status, education, and body mass index were collected during the 1994 survey. Women were classified as ever or never smokers based on information on smoking status collected in the 1994 questionnaire. We also evaluated current and former versus never smoking (based on the 1994 questionnaire response). Data on parity, tubal ligation, unilateral oophorectomy, oral contraceptives, and HRT were collected during all three NCI surveys, and there was also information on oral contraceptive use from the earlier studies conducted during the 1970s and 1980s.

The amount of detail on DES dose and timing of first exposure during gestation varied among the four cohorts. There was no information on dose or timing of exposure for the Women's Health Study cohort. The Dieckmann cohort followed the high-dose regimen recommended by Smith and Smith (23Go), and most women in the exposed group received a total cumulative dose of approximately 12 g. For this cohort, documentation of the amount of DES and the timing during gestation was excellent, and compliance with the medication was monitored in urine by the use of a dye in both DES and placebo pills. Women in the Horne cohort also tended to be given high doses of DES, and information on dose and timing was nearly complete. The amount of information on the dose and timing of exposure in the DESAD cohort was less complete, with an estimated cumulative minimal dose available for 33 percent, and timing of first exposure documented for 79 percent, of those exposed. Overall, DES dose was available for 38 percent and timing of exposure during gestation was available for 75 percent of the exposed women in the combined cohorts.

Survival analysis methods were used to compare the distribution of age at natural menopause according to DES and other covariates. Age at natural menopause was treated as the "time to event," and life-table methods were used to calculate mean and median ages at natural menopause. For univariate analyses, Kaplan-Meier survival curves and log-rank tests were used to identify factors associated with earlier or later age at menopause. Cox proportional hazards modeling was used to calculate hazard ratios and 95 percent confidence intervals for the occurrence of menopause while controlling for potential confounding variables (24Go). Variables were evaluated in the multivariate models if they were of a priori interest or showed a relation with age at menopause in univariate analyses, and they were retained in the final models if they affected the estimates for DES exposure by at least 10 percent. Log-log survival plots were examined to assess departure from the proportional hazards assumption. All analyses were conducted in the combined cohorts, and within the individual cohorts. To address our concern that initiation of HRT over follow-up may be related to the onset of menopausal symptoms and may differ by exposure status, we performed additional analyses in which we 1) excluded women who reported HRT use before menopause and 2) reclassified women who reported HRT use as experiencing menopausal events instead of censored observations.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Over half of the cohort of both exposed and unexposed women were still premenopausal at their last follow-up (table 1). Exposed and unexposed women were equally likely to have had a surgical menopause (19 percent), and 16 percent of the exposed and 17 percent of the unexposed had experienced natural menopause. Use of HRT before menopause was not common and occurred in similar proportions of exposed and unexposed women. Exposed women were somewhat younger; the mean ages of the exposed and unexposed women in 2001 were 47.2 and 48.5 years, respectively. Compared with unexposed women, exposed women had higher levels of education, were less likely to have ever smoked, and had fewer children and a later age at first birth (table 2). They were slightly more likely to have had a unilateral oophorectomy and less likely to have had a tubal ligation. Use of oral contraceptives and HRT was similar in the two groups.


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  		TABLE 1. Menopausal status* of DES{dagger}-exposed and unexposed daughters, National Cancer Institute's DES Follow-up Study, United States, 1994–2001

 

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  		TABLE 2. Selected characteristics of DES*-exposed and unexposed daughters, National Cancer Institute's DES Follow-up Study, United States, 1994–2001

 
Compared with unexposed women, DES-exposed women were approximately 50 percent more likely to have reached natural menopause at each age (figure 1). The average age at menopause was 52.2 years in unexposed women and 51.5 years in exposed women. The results varied somewhat by cohort (table 3). Exposed women in the Dieckmann cohort were more than twice as likely as unexposed women to have undergone natural menopause. DES-exposed women in the DESAD cohort were approximately 40 percent more likely to have experienced menopause, and those in the Women's Health Study cohort were about 30 percent more likely to be postmenopausal compared with unexposed women. Women in the Horne cohort were younger on average; therefore, fewer of them had experienced natural menopause (n = 2), so the estimate was very unstable. When the analysis was repeated by excluding the Horne cohort, the results were similar (hazard ratio = 1.50, 95 percent confidence interval: 1.28, 1.75). The Wald test for heterogeneity of the effect of DES among the cohorts was borderline significant (p = 0.05). The heterogeneity appeared to be due primarily to the Dieckmann cohort; the effect of DES in this cohort versus all of the other cohorts combined was highly significant (p = 0.008). This difference may reflect a dose effect, rather than a group effect, because members of the Dieckmann cohort were exposed to higher doses of DES.


Figure 1
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  		FIGURE 1. Age at natural menopause by diethylstilbestrol (DES) exposure, National Cancer Institute's DES Follow-up Study, United States, 1994–2001.

 

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  		TABLE 3. Hazard ratios and 95% confidence intervals for the occurrence of natural menopause among DES*-exposed compared with unexposed daughters, by individual cohort and in the combined cohort,{dagger} National Cancer Institute's DES Follow-up Study, United States, 1994–2001

 
Adjustment for potential confounding variables had little effect on the results, with the exception of adjustment for year of birth and cohort. The crude hazard ratio for DES exposure was 1.27 (95 percent confidence interval: 1.10, 1.45) compared with 1.49 (95 percent confidence interval: 1.28, 1.74) after adjustment for year of birth and cohort. In a model containing smoking status (ever vs. never), age at menarche (≤11, 12–13, ≥14 years), unilateral oophorectomy, and educational level (≤12 years, some college, college graduate, graduate school), in addition to year of birth and cohort, the effect estimate for DES in the combined cohorts was similar (hazard ratio = 1.50, 95 percent confidence interval: 1.28, 1.74). Assessment of current and former versus never smoking in this model also had little effect on the results for DES (hazard ratio = 1.48, 95 percent confidence interval: 1.27, 1.72). Similarly, when parity (parous vs. nulliparous), birth weight (<3,000, 3,000–3,499, ≥3,500 g), oral contraceptive use (ever vs. never), body mass index (<21, 21–22, 23–25, ≥26 kg/m2), tubal ligation, and marital status were added to the model containing the variables listed above, the hazard ratio was 1.45 (95 percent confidence interval: 1.22, 1.71). We also found no confounding or effect modification according to whether a woman had experienced infertility (data not shown). Adjusting for mother's age at menopause (ascertained by questionnaire for the mothers in previous studies) among the subset of daughters for whom these data were available (n = 2,389 or 41 percent of the total) also had no material effect on the estimate for DES exposure (data not shown). Log-log survival plots did not suggest a violation of the proportional hazards assumption.

Details on the cumulative dose of DES received during pregnancy were available for less than half of the women in the three original cohorts; nevertheless, in this subset, there was an increasing risk of earlier natural menopause at higher cumulative doses (table 4). Compared with unexposed women, women who received a total dose of less than 2,500 mg had a nonsignificant 19 percent increase in the risk of menopause, those who received 2,500–10,000 mg were 1.4 times as likely to have experienced menopause, and those in the highest dose group (>10,000 mg) were more than twice as likely to have experienced natural menopause (trend test among the exposed only, p < 0.001). The effect of dose remained significant once gestational age at first exposure was controlled for in the model. In contrast, there did not appear to be a trend toward higher risk of early menopause with earlier gestational age at first exposure to DES.


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  		TABLE 4. Hazard ratios and 95% confidence intervals for the occurrence of natural menopause, by total cumulative dose and gestational age at first DES* exposure{dagger},{ddagger} National Cancer Institute's DES Follow-up Study, United States, 1994–2001

 
The analyses were repeated by excluding women who had been censored because they reported use of HRT, including birth control pills for menopausal symptoms, prior to menopause, with similar results (hazard ratio = 1.55, 95 percent confidence interval: 1.33, 1.81). When the analyses treated these same women as experiencing menopausal events at the age of first use of HRT, the results were also quite similar (hazard ratio = 1.41, 95 percent confidence interval: 1.24, 1.61). We also repeated the analysis by excluding women who reported ever having used hormone therapy, including birth control pills for menopause, and drugs such as tamoxifene or raloxifene, with no material change in effect (hazard ratio = 1.52, 95 percent confidence interval: 1.20, 1.93). Adjustment for ever use of HRT also did not change the effect estimate for DES exposure (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Our study found that, compared with unexposed women, women who were exposed to DES in utero tended to experience earlier natural menopause. The effect of DES increased with cumulative doses and was greatest among members of the Dieckmann cohort, who were exposed to high doses during a clinical trial of DES conducted in the early 1950s.

To our knowledge, this is the first study that has found an effect of a prenatal exposure on age at menopause. The development of ovarian follicles reaches a peak of approximately 6–7 million at about the 20th week of gestation and after that begins a rapid decline through a process called atresia, until about 1–2 million remain at birth. By puberty, only about 500,000 follicles remain in the ovaries, and, during a woman's lifetime, an average of 400–500 follicles are ovulated (25Go), although a recent study in mice suggests that follicles can be regenerated over the lifespan (26Go). Some studies suggest that menopause occurs when the size of the follicle reserve falls to about 1,100 (27Go). Theories about the causes of variation in age at menopause include differences in the size of the initial pool of follicles, the rate of follicle depletion through either ovulation or atresia, and possibly alterations in neuroendocrine function and steroid hormone metabolism (28Go).

Several studies in animals support the biologic plausibility of an effect of DES on age at menopause. McLachlan (19Go) found that the number of ova that could be harvested from DES-exposed mice after ovulation induction was only 30 percent of that in the control group. Other studies have reported advancements in follicle development (29Go, 30Go), a reduction in number of primordial follicles (30Go), and a greater number of polyovular follicles in DES-exposed animals (31Go). In addition, DES induces transient changes in gene expression during gestation that have been shown to have permanent effects on subsequent development of the reproductive tract (32Go). These changes could be involved in follicle development, rate of atresia, or patterns of secretion or metabolism of steroid hormones. DES given in utero or during the first year of life caused major changes in endocrine function in primates (33Go) and was shown to increase thyroid function in rats (30Go).

A limitation of our study is possible misclassification of age at menopause. Unexposed women are slightly older than exposed women, and a higher proportion reported their age at menopause retrospectively on the 1994 questionnaire (31 percent vs. 19 percent). On the other hand, younger women may have more menstrual cycle variability during the menopausal transition. Both of these scenarios could lead to differential misclassification of menopausal age and might have affected our results for the DESAD, Women's Health Study, and Horne cohorts. However, in the Dieckmann cohort, the age distribution of the exposed and unexposed women is virtually identical; therefore, differential misclassification of menopausal age seems unlikely in this cohort. There also might have been some misclassification of HRT or oral contraceptive use that could have led to misclassification of age at menopause. When we conducted sensitivity analyses by excluding women who were currently taking hormones or by treating them as having menopausal outcomes, the results did not change appreciably.

Another limitation of the study is the lack of detailed dose information for most of those exposed to DES. In the Dieckmann cohort, which had the highest levels of exposure, documentation of dose was complete. However, in the DESAD cohort, where dose was more variable because of medical practices in different areas of the country, dose information was incomplete for many participants. The dose abstraction charts often had several detailed entries and then were coded as "no further information" in later gestation. This shortcoming limited our ability to evaluate dose-response effects. Even so, we did find a strong trend of earlier menopause among women with higher levels of DES exposure in the subset of women for whom we had complete dose information.

Strengths of our study include the prospective design, the large number of menopausal events, and reasonably good response rates. The NCI cohort is the only existing, large cohort of DES-exposed individuals that includes medical record documentation of exposure. Evaluation of age at menopause close in time to its occurrence likely minimized misclassification due to poor recall. The inclusion of a cohort derived from a clinical trial, in addition to observational cohorts, also minimized the possibility that the effects on daughters' age at menopause were due to confounding by indication. Furthermore, adjustment for mother's age at menopause in a subset of the cohort did not change the results.

Many studies suggest that fetal exposures are important in a variety of adult diseases and conditions (34Go), but ours is the first known to suggest that in utero exposures affect a woman's age at menopause. More than half of the cohort is still premenopausal, so this question should be reevaluated when the majority of the women have undergone menopause to ensure that the finding is still evident as the cohort ages. Future studies should evaluate other in utero exposures, such as other endocrine-disrupting compounds or maternal smoking, in relation to reproductive lifespan.


   ACKNOWLEDGMENTS
 
Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. van der Schouw YT, van der Graaf Y, Steyerberg EW, et al. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996;347:714–18.[CrossRef][Web of Science][Medline]
  2. Kritz-Silverstein D, Barrett-Connor E. Early menopause, number of reproductive years, and bone mineral density in postmenopausal women. Am J Public Health 1993;83:983–8.[Abstract/Free Full Text]
  3. Cooper GS, Sandler DP. Age at natural menopause and mortality. Ann Epidemiol 1998;8:229–35.[CrossRef][Web of Science][Medline]
  4. Jacobsen BK, Heuch I, Kvale G. Age at natural menopause and all-cause mortality: a 37-year follow-up of 19,731 Norwegian women. Am J Epidemiol 2003;157:923–9.[Abstract/Free Full Text]
  5. Trichopoulos D, MacMahon B, Cole P. Menopause and breast cancer risk. J Natl Cancer Inst 1972;48:605–13.[Web of Science][Medline]
  6. Kalandidi A, Tzonou A, Lipworth L, et al. A case-control study of endometrial cancer in relation to reproductive, somatometric, and life-style variables. Oncology 1996;53:354–9.[Web of Science][Medline]
  7. Harlow BL, Signorello LB. Factors associated with early menopause. Maturitas 2002;42(suppl 1):S87–93.
  8. Gold EB, Bromberger J, Crawford S, et al. Factors associated with age at natural menopause in a multiethnic sample of midlife women. Am J Epidemiol 2001;153:865–74.[Abstract/Free Full Text]
  9. Stanford JL, Hartge P, Brinton LA, et al. Factors influencing the age at natural menopause. J Chronic Dis 1987;40:995–1002.[CrossRef][Web of Science][Medline]
  10. Whelan EA, Sandler DP, McConnaughey DR, et al. Menstrual and reproductive characteristics and age at natural menopause. Am J Epidemiol 1990;131:625–32.[Abstract/Free Full Text]
  11. Cresswell JL, Egger P, Fall CH, et al. Is the age of menopause determined in-utero? Early Hum Dev 1997;49:143–8.[CrossRef][Web of Science][Medline]
  12. Hornsby PP, Wilcox AJ, Herbst AL. Onset of menopause in women exposed to diethylstilbestrol in utero. Am J Obstet Gynecol 1995;172:92–5.[CrossRef][Web of Science][Medline]
  13. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 1971;284:878–81.[Web of Science][Medline]
  14. Palmer JR, Hatch EE, Rao RS, et al. Infertility among women exposed prenatally to diethylstilbestrol. Am J Epidemiol 2001;154:316–21.[Abstract/Free Full Text]
  15. Kaufman RH, Adam E, Hatch EE, et al. Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring. Obstet Gynecol 2000;96:483–9.[CrossRef][Web of Science][Medline]
  16. Hornsby PP, Wilcox AJ, Weinberg CR, et al. Effects on the menstrual cycle of in utero exposure to diethylstilbestrol. Am J Obstet Gynecol 1994;170:709–15.[Web of Science][Medline]
  17. Wu CH, Mangan CE, Burtnett MM, et al. Plasma hormones in DES-exposed females. Obstet Gynecol 1980;55:157–62.[Web of Science][Medline]
  18. Peress MR, Tsai CC, Mathur RS, et al. Hirsutism and menstrual patterns in women exposed to diethylstilbestrol in utero. Am J Obstet Gynecol 1982;144:135–40.[Web of Science][Medline]
  19. McLachlan JA, Newbold RR, Shah HC, et al. Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertil Steril 1982;38:364–71.[Web of Science][Medline]
  20. Hatch EE, Palmer JR, Titus-Ernstoff L, et al. Cancer risk in women exposed to diethylstilbestrol in utero. JAMA 1998;280:630–4.[Abstract/Free Full Text]
  21. Dieckmann WJ, Davis ME, Rynkiewicz LM, et al. Does the administration of diethylstilbestrol during pregnancy have therapeutic value? Am J Obstet Gynecol 1953;66:1062–81.[Web of Science][Medline]
  22. Colton T, Greenberg ER, Noller K, et al. Breast cancer in mothers prescribed diethylstilbestrol in pregnancy. Further follow-up. JAMA 1993;269:2096–100.[Abstract/Free Full Text]
  23. Smith OW, Smith GV. The influence of diethylstilbestrol on the progress and outcome of pregnancy as based on a comparison of treated with untreated primigravidas. Am J Obstet Gynecol 1949;58:994–1009.[Web of Science][Medline]
  24. Cox DR. Regression models and life tables (with discussion). J R Stat Soc (B) 1972;34:187–220.
  25. Faddy MJ, Gosden RG. A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod 1996;11:1484–6.[Abstract/Free Full Text]
  26. Johnson J, Bagley J, Skaznik-Wikiel M, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 2005;122:303–15.[CrossRef][Web of Science][Medline]
  27. Gosden RG, Faddy MJ. Biological bases of premature ovarian failure. Reprod Fertil Dev 1998;10:73–8.[CrossRef][Medline]
  28. Wise PM, Krajnak KM, Kashon ML. Menopause: the aging of multiple pacemakers. Science 1996;273:67–70.[Abstract]
  29. Wordinger RJ, Derrenbacker J. In utero exposure of mice to diethylstilbestrol alters neonatal ovarian follicle growth and development. Acta Anat (Basel) 1989;134:312–18.[Web of Science][Medline]
  30. Yamamoto M, Shirai M, Sugita K, et al. Effects of maternal exposure to diethylstilbestrol on the development of the reproductive system and thyroid function in male and female rat offspring. J Toxicol Sci 2003;28:385–94.[CrossRef][Medline]
  31. Iguchi T, Takasugi N, Bern HA, et al. Frequent occurrence of polyovular follicles in ovaries of mice exposed neonatally to diethylstilbestrol. Teratology 1986;34:29–35.[Medline]
  32. Mericskay M, Carta L, Sassoon D. Diethylstilbestrol exposure in utero: a paradigm for mechanisms leading to adult disease. Birth Defects Res A Clin Mol Teratol 2005;73:133–5.[CrossRef][Web of Science][Medline]
  33. Fuller GB, Yates DE, Helton ED, et al. Diethylstilbestrol reversal of gonadotropin patterns in infant rhesus monkeys. J Steroid Biochem 1981;15:497–500.[CrossRef][Web of Science][Medline]
  34. Barker DJ, Eriksson JG, Forsen T, et al. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002;31:1235–9.[Abstract/Free Full Text]

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