American Journal of Epidemiology Advance Access originally published online on January 11, 2008
American Journal of Epidemiology 2008 167(6):727-733; doi:10.1093/aje/kwm351
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ORIGINAL CONTRIBUTIONS |
The Association between In Utero Cigarette Smoke Exposure and Age at Menopause
1 Department of Obstetrics and Gynecology, Tufts-New England Medical Center, Boston, MA
2 Department of Epidemiology, Boston University School of Public Health, Boston, MA
3 Information Management Services, Rockville, MD
4 Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH
5 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
6 Department of Obstetrics and Gynecology, The Methodist Hospital, Houston, TX
7 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC
8 Department of Pathology, Duke University Medical Center, Durham, NC
9 Department of Epidemiology and Biostatistics, Slone Epidemiology Unit, Boston University School of Public Health, Brookline, MA
10 Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
Correspondence to Dr. William C. Strohsnitter, Department of Obstetrics and Gynecology, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111 (e-mail address: Wstrohsnitter{at}tufts-nemc.org).
Received for publication July 4, 2007. Accepted for publication November 6, 2007.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Menopause onset, on average, occurs earlier among women who smoke cigarettes than among women who do not smoke. Prenatal smoke exposure may also influence age at menopause through possible effects on follicle production in utero. Smoking information was obtained from the mothers of 4,025 participants in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project, a US study begun in 1975 to examine the health effects of prenatal diethylstilbestrol exposure. Between 1994 and 2001, participants provided information on menopausal status. Cox proportional hazards modeling compared the probability of menopause among participants who were and were not prenatally exposed to maternal cigarette smoke. Participants prenatally exposed to maternal cigarette smoke were more likely than those unexposed to be postmenopause (hazard ratio = 1.21, 95% confidence interval: 1.02, 1.43). The association was present among only those participants who themselves had never smoked cigarettes (hazard ratio = 1.38, 95% confidence interval: 1.10, 1.74) and was absent among active smokers (hazard ratio = 1.03, 95% confidence interval: 0.81, 1.31). In this cohort of participants predominantly exposed to diethylstilbestrol, results suggest that prenatal exposure to maternal cigarette smoke may play a role in programming age at menopause. The possibility that active cigarette smoking modifies this effect is also suggested.
cohort studies; diethylstilbestrol; menopause; prenatal exposure delayed effects; smoke, smoking
Abbreviations: CI, confidence interval; DES, diethylstilbestrol; DESAD, National Cooperative Diethylstilbestrol Adenosis; HR, hazard ratio
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Menopause onset, on average, occurs earlier among women who smoke cigarettes than among women who do not smoke (1–5). Possible explanations include ovarian follicle loss near menopause resulting from exposure to toxins in cigarette smoke (1, 6, 7) or the effect of cigarette smoke on estrogen production (2). Although the number of follicles available throughout a woman's reproductive life is generally thought to be determined at birth (8), little is known about prenatal factors that may influence this number. In one study, earlier age at menopause was associated with decreased birth length and decreased weight at birth in relation to length (9). These findings, however, were not replicated in a study of twins (10). Recently, Hatch et al. (11) observed that women exposed prenatally to diethylstilbestrol (DES) experienced menopause, on average, earlier than unexposed women, raising the possibility that prenatal hormonal exposure may influence age at menopause.
Cigarette smoking during pregnancy has been associated with decreased maternal levels of estradiol, estriol, and human chorionic gonadotropin (12–15). It has also been associated with increased levels of alpha feto-protein (12), believed to have antiestrogenic properties (16). If in utero ovarian follicle formation is hormone dependent, women prenatally exposed to maternal cigarette smoke, compared with women who did not incur such exposure, may also have a different average age at menopause. This study involved follow-up of 4,025 women for 25 years and investigated the association between prenatal cigarette smoke exposure and age at menopause. We also examined the relation between prenatal cigarette smoke exposure and active cigarette smoking in determining age at menopause.
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MATERIALS AND METHODS |
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Study participants
In 1994, the National Cancer Institute combined several previously assembled cohorts for continued follow-up of health effects associated with prenatal DES exposure (17). The current study was confined to participants in the largest cohort, the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project, for whom prenatal exposure to maternal cigarette smoke was known. Initially, DES-exposed and -unexposed women were recruited into this cohort for follow-up of gynecologic changes (18). From 1975 through 1982, women were recruited at the following study centers: the Mayo Clinic, Rochester, Minnesota; the Gundersen Clinic, LaCrosse, Wisconsin; Baylor College of Medicine, Houston, Texas; the University of Southern California, Los Angeles, California; and the Massachusetts General Hospital, Boston, Massachusetts.
DES-exposed women were identified via review of prenatal medical records, or they were physician or self-referred. Inclusion required all DES-exposed women to have documentation of prenatal DES exposure (n = 4,007). Recruited women who were not prenatally exposed to DES (n = 1,031) either were identified by prenatal medical records or were unexposed siblings of exposed participants (n = 203 or 19.7 percent of unexposed women). The women in the DESAD cohort were between the ages of 9 and 39 years when they were recruited (median recruitment age = 22 years) and were born between 1939 and 1968 (median birth year = 1953). Of the 5,038 women recruited, 4,930 (97.9 percent) provided more than 1 year of follow-up. Informed consent was indicated by the participants by completing follow-up questionnaires, and all participants were followed in accordance with the policies of the institutional review boards at the National Cancer Institute and the respective recruiting centers.
Exposure determination
At recruitment, participants' mothers reported whether they smoked cigarettes while pregnant with the participant and, if so, the number smoked daily. Among the 4,930 women who eventually provided more than 1 year of follow-up, the mothers of 4,635 of these participants (94.0 percent) provided information on whether they smoked while pregnant with the participant. To determine whether there was a dose-response relation between prenatal cigarette smoke exposure and age at menopause, exposure levels were dichotomized at 15 cigarettes per day, the median number of cigarettes reported by those participants' mothers who smoked during the index pregnancy. From 1976 through 1989, participants were annually followed for changes in their health status or habits by completing a written questionnaire. Participants finished the questionnaires and mailed them back to the respective study centers. If, after two requests, the participant had not returned her questionnaire, it was administered via phone interview by a trained study assistant. Questionnaires were again administered in 1994, 1997, and 2001.
Smoking habits of the participants themselves were determined through 1994, and the effect of active cigarette smoking on age at menopause was also estimated in the current study. Duration of smoking was dichotomized with a cutoff of 14 years, the median smoking duration reported by active smokers through 1994. Only those participants who completed the 1994 questionnaire, when smoking history was last determined (n = 4,025 or 80 percent of the initial DESAD cohort), were included in the current study.
Outcome determination
Follow-up of menstrual status occurred in 1994, 1997, and 2001, and this follow-up has been described previously (11). Natural menopause was considered to have occurred if a participant reported amenorrhea for 12 consecutive months and had not had a bilateral oophorectomy or a hysterectomy. In 1994, participants were asked whether their menstrual periods had stopped and, if so, at what age. They were also asked whether cessation occurred naturally or because of surgery. In 1997 and 2001, participants were asked for an update on their menstrual status and the date of their last period. If applicable, the dates of oophorectomy and hysterectomy were also asked. Age at natural menopause was calculated by subtracting the participant's date of birth from the date of her last reported period.
Statistical analysis
Cox proportional hazards modeling was used to estimate the effect of prenatal cigarette smoke exposure on age at menopause (19). Participants who had not had a natural menopause were censored at the age of their last reported menstrual period or bilateral oophorectomy/hysterectomy. A total of 174 participants who used hormone replacement therapy before their periods stopped were censored at the age they began treatment since such use can mask true menopause. Factors previously reported to influence age at menopause and considered potential confounders include body mass index (weight in kilograms divided by square of height in meters), attained education, age at menarche, marital status (1, 20), and pregnancy and birth histories (1). History of unilateral oophorectomy, hormone replacement therapy, and oral contraceptive use (1) was also considered. Body mass index, attained education, age at menarche, and marital status were determined from responses to the 1994 questionnaire. Pregnancy and birth histories were determined from responses to the 1994 and 1997 questionnaires, and oophorectomy, hormone replacement therapy use, and oral contraceptive use histories were updated regularly from 1994 through 2001.
There were 476 women who still smoked in 1994, when smoking history was determined last. Consequently, the actual age at which these participants stopped smoking, if any, was unknown. In addition, 328 women reported smoking cessation in 1994 but had stopped for less than 5 years; they may have resumed the habit later. To address the possibility of misclassification with regard to smoking duration among women who possibly relapsed and those who had not stopped by 1994, the data were reanalyzed assuming that women in both of these groups continued to smoke through 2001, when menopause status was last determined.
Differences in the distribution of dichotomous variables between the prenatal and active smoking groups were tested by using the chi-squared test for independence, and Student's t test was used to test the difference in distribution of continuous variables (21). Potential confounding variables were included in the model if they changed either the hazard ratio or the limits of its associated 95 percent confidence interval by more than 10 percent. Violation of the proportional hazards model was evaluated by plotting the attained age by the negative logarithm of the cumulative survival logarithm. The test for interaction between two variables on the multiplicative scale was conducted by adding a product term containing the two variables to the proportional hazards model. Life-table methods were used to compare the median age at natural menopause between exposure groups.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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For 594 (14.8 percent) of the 4,025 women included in the current analysis, their periods had ceased naturally for at least 12 months by 2001. A large percentage of women (79.9 percent) recruited into the DESAD cohort were prenatally exposed to DES, since the cohort was originally assembled to examine gynecologic changes among women with such exposure. Among the women included in the current analysis, 80.1 percent were prenatally exposed to DES. The percentages of DES-exposed women among those who were and were not prenatally exposed to maternal cigarette smoke were 80.2 percent and 80.0 percent, respectively.
The characteristics of women included in the analysis were compared with those of the women (n = 610) who had to be excluded because of lack of information after 1989. Thirty-seven percent of the included women were prenatally exposed to cigarette smoke, as were 39.9 percent of the excluded women. Among those included in this analysis, 80.1 percent were prenatally DES exposed, and 78.7 percent of those excluded were DES exposed. Excluded women were more likely to have been active smokers in 1989 (48.6 percent) than those who were included (44.6 percent). In 1989, the mean ages of the women included in and excluded from the current analysis were 34.7 years and 34.4 years, respectively.
The distribution was similar for most potential confounders of the association between prenatal cigarette smoke exposure and age at menopause, but there were differences between the two groups with regard to active smoking, age at first birth, and year of participant's birth. Mean age at recruitment among women prenatally exposed to maternal cigarette smoke was 22.0 years and was 22.3 years among women not so exposed (table 1). More potential confounders were unequally distributed between participants who themselves did and did not smoke cigarettes. Among the 1,802 participants who reported smoking, 734 (40.7 percent) were prenatally exposed to maternal cigarette smoke compared with 756 (34.0 percent) women who did not smoke cigarettes. There were 524 (23.6 percent) women nonsmokers born before or during 1950 and 508 (28.2 percent) active smokers born during this period. Among parous women smokers, 366 (30.4 percent) had their first child after the age of 30 years, and 499 (33.8 percent) parous women nonsmokers had their first child after this age. Of the women who reported ever smoking cigarettes, 365 (20.3 percent) had completed more than 4 years of college compared with 687 (30.1 percent) of women who did not smoke. Oral contraceptive use (85.6 percent) was higher among women smokers than among women nonsmokers (78.6 percent). In addition, hormone therapy use was greater among smokers (36.3 percent) than among nonsmokers (32.6 percent) (data not shown).
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No potential confounder, including prenatal DES exposure and active cigarette smoking, appreciably changed the estimate of the effect of prenatal cigarette smoke exposure on age at menopause. Consequently, the unadjusted effect estimate is presented here. Participants prenatally exposed to maternal cigarette smoke were 21 percent more likely than unexposed women to be postmenopausal at any given age (hazard ratio (HR) = 1.21, 95 percent confidence interval (CI): 1.02, 1.43) (table 2). The effect estimates were constant regardless of the amount of prenatal cigarette smoke exposure and whether or not the participant was exposed prenatally to DES (table 2). The exposure-specific linear plots of the –log (log cumulative survival) versus age were both linear and parallel, indicating that the proportional hazards assumption was not violated (results not shown).
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The effect of prenatal cigarette smoke exposure on age at menopause appeared different among participants who never smoked and those who did. No association was found between prenatal cigarette smoke exposure and age at menopause among women who reported smoking (HR = 1.03, 95 percent CI: 0.81, 1.31) (table 2). There appeared, however, to be an association for participants who reported no active smoking (HR = 1.38, 95 percent CI: 1.10, 1.74) (table 2).
The magnitude of association between active smoking and age at menopause resembled that for prenatal cigarette smoke exposure (HR = 1.20, 95 percent CI: 1.02, 1.41). Again, the effect estimate did not change after controlling for potential confounders including prenatal DES exposure. In this instance, however, a dose-response relation between active smoking and menopause risk was apparent. The association relative to nonsmokers appeared stronger among participants who actively smoked cigarettes for 14 years or more (HR = 1.47, 95 percent CI: 1.21, 1.78) versus participants who smoked for fewer years (HR = 0.97, 95 percent CI: 0.78, 1.19) (results not shown).
Prenatal cigarette smoke exposure also affected the association between active smoking and age at menopause. The association was absent among participants prenatally exposed to maternal cigarette smoke (HR = 1.00, 95 percent CI: 0.77, 1.30) but was apparent among participants not prenatally exposed to maternal cigarette smoke (HR = 1.33, 95 percent CI: 1.08, 1.64). Among participants not prenatally exposed to maternal cigarette smoke, no association was found between active smoking for fewer than 14 years and age at menopause relative to participants who never smoked (HR = 1.00, 95 percent CI: 0.76, 1.30), but an association was observed among long-term (14 years or longer) smokers relative to participants who never smoked (HR = 1.79, 95 percent CI: 1.40, 2.28) (results not shown).
We found no appreciable shift toward long-term smoking duration when women whose smoking status after 1994 was uncertain were assumed to have continued smoking through 2001. Only 3.0 percent of current smokers in 1994 who had smoked for fewer than 14 years were reclassified as smokers for 14 or more years. In addition, when women who stopped smoking for 5 or fewer years in 1994 were assumed to have relapsed and smoked through 2001, only 13.7 percent of these women shifted from the short-term to the long-term smoking categories. Consequently, there was no change in the estimate of effect of smoking duration on age at menopause when these women were reclassified.
The median age at menopause among participants prenatally exposed to maternal cigarette smoke was 52.2 versus 52.7 years for participants who were not so exposed. This difference disappeared among participants who were active smokers but was evident among participants who never smoked. Furthermore, the median age at menopause among participants who were not prenatally exposed to maternal cigarette smoke but who smoked for 14 years or more was 50.6 years, 2.6 years younger than participants who were not prenatally exposed to maternal cigarette smoke and never actively smoked (table 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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This study suggests that prenatal exposure to maternal cigarette smoke may affect age at menopause for female offspring. Numerous studies have indicated that maternal cigarette smoking alters the prenatal hormonal environment (12–15). In the current study within a cohort of women that was 80 percent DES exposed, women prenatally exposed to maternal cigarette smoke had, on average, an earlier menopause than women who were not. This association was strongest among participants who never smoked and disappeared among active smokers. Furthermore, the well-documented association between active smoking and age at menopause (1–5) was not present among women prenatally exposed to maternal cigarette smoke.
The information pertaining to maternal cigarette smoke exposure is accurate and relatively complete since it was obtained directly from the mother, and 94 percent of DESAD participants' mothers provided this information. Exposure information was also provided before follow-up of menopause began, so there is no likelihood that reporting of cigarette smoke exposure was influenced by age at menopause. The cigarette smoking history provided by the mother was likely to be consistent throughout the pregnancy since most of the pregnancies occurred between 1940 and 1960, when mothers were not likely to change their cigarette smoking habits during pregnancy for health reasons.
The study also has some limitations. It is not known for how long some participants actually smoked. Women may have stopped smoking after their smoking history was last obtained in 1994, and former smokers may have resumed smoking after this time. There was, however, very little reclassification to the longer-term smoking category when these women were assumed to have smoked through 2001. While maternal cigarette smoke exposure was determined before menopause, it was on average also determined 22 years after birth, the mean age at the participant's recruitment into the study. It is unlikely, however, that differential recall bias was operating in this instance since the mean age at recruitment in the two prenatal smoke exposure groups was similar.
Selective forces could have biased the results of this study. Of the 4,635 women eligible for follow-up in this study, 610 (13 percent) withdrew from the study before 1994, when menopause status was first determined. Nonetheless, the distribution of women who were and were not prenatally exposed to maternal cigarette smoke was about the same among those women who were and were not followed after 1994. The distribution of possible determinants of age at menopause, such as age and smoking status in 1989, was reasonably similar among those who did and did not complete follow-up.
Confounding did not appear to be operating in this study. Control for potential confounders did not appreciably change the estimate of the effect of prenatal or active smoke exposure on menopause age. Control for confounding, however, may have been incomplete because of the limited information available on some of these factors. Finally, since most of the women in the cohort were prenatally exposed to DES, the results of this study may not be applicable to other female populations. The estimates of the effect of prenatal cigarette smoke on age at menopause specific to DES exposure, however, appeared similar.
Menopause, the cessation of menses for at least 12 months, is attributable mostly to depletion of functional primary follicles (22), but, recently, a hormonal determinant has also been suspected (23). It is generally believed that the number of primordial follicles that develop within the fetal ovary limits the number of functional follicles during a woman's reproductive life (8). The possibility that prenatal cigarette smoke exposure is related to age at menopause is consistent with what is known about the effect of smoking on the intrauterine environment and the availability of functional oocytes during the adult reproductive life. Maternal smoking may influence maternal hormone levels (12–15). These levels in turn may affect the function of primary follicles later in the daughter's reproductive life (24). Numerous studies have indicated that estradiol (13, 14) and estriol (12, 15) levels are reduced in women who smoke during pregnancy. The decrease especially in estriol levels may be greater in women who smoke few cigarettes (10 or fewer per day) than in women who do not smoke at all or are heavier smokers (12, 14). Levels of alpha-fetoprotein increase and human chorionic gonadotropin levels decrease in women who smoke relative to women who do not (12). Maternal cigarette smoking may therefore influence numerous intrauterine hormone and local growth factor levels.
The intrauterine environment may in turn affect the production of functional oocytes, and consequently the age at menopause. Studies of rat oocytes harvested at birth suggest that elevated levels of maternal estradiol during pregnancy might prevent primordial follicles from prematurely developing into primary follicles that later produce sex hormones during the menstrual cycle (24). Reduced estradiol levels in mothers who smoke may limit this arrest. Consequently, more primordial follicles in an environment with reduced estradiol may prematurely develop into nonfunctional, more advanced follicles. Although maternal smoking may lower pregnancy estrogen levels, the reduction is not more pronounced with increasing amounts of maternal cigarette smoke. This finding was observed in at least one clinical study (12). Our observation that age at menopause did not decrease further with increasing exposure to maternal cigarette smoke is consistent with that study's finding.
The effect of active cigarette smoking on age at menopause is thought to be mediated through components of active cigarette smoke. These agents are thought to be toxic to oocytes during reproductive life and may precipitate earlier menopause in women so exposed relative to women who are not (6, 7). The influence of active smoking on age at menopause might also be mediated through the antiestrogenic effect of components of cigarette smoke (2). Whatever toxic effects cigarette smoke have on oocyte life, the limited data in the current study raise the possibility that they are imparted only once. There was no apparent effect of active cigarette smoking on age at menopause observed among women prenatally exposed to maternal cigarette smoke. At this juncture, any discussion regarding the interaction of these two exposures on age at menopause is speculative. Very few studies have addressed the possibility that menopause onset has a prenatal determinant (9–11). Our study also suggests that menopause etiology may have a prenatal component; however, further studies are needed to more specifically establish the influence of intrauterine environment on duration of reproductive life.
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ACKNOWLEDGMENTS |
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This work was supported by National Cancer Institute contacts N01-CP-01288, N01-CP-01289, N01-CP-01290, and N01-CP-01012-21.
The authors are grateful for the diligent efforts of study coordinators Mary Ziegler, Ann Urbanovitch, Elizabeth Barnard, and Helen Bond. They also acknowledge the invaluable help of Pat Cody, DES Action, Susan Helmrich, and Margaret Lee Braun. They thank the staff at Westat Inc., including Bob Saal and Cathy Ann Gundemeyer, for study-wide coordination efforts.
Conflict of interest: none declared.
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