- Email: [email protected]
Onset of menopause in women exposed to diethylstilbestrol in utero
Gynecology
Onset of menopause in women exposed to diethylstilbestrol in utero Paige P. Hornsby, Research Triangle
PhD,” Allen J. Wilcox, Park, North Carolina,
MD, PhD,” and Arthur
and Chicago,
L. Herb&,
MD’
Illinois
OBJECTIVES: As part of a larger health survey, we sought to determine whether prenatal exposure to diethylstilbestrol is associated with onset of early menopause or menopausal symptoms. STUDY DESIGN: Diagnosis of premature ovarian failure and symptoms of menopause were determined in a telephone interview with 542 women whose mothers participated in a randomized clinical trial of the use of diethylstilbestrol in pregnancy in the early 1950-s. These women were aged 37 to 39 at the time of the interview. Medical records were obtained to confirm diagnosis of premature ovarian failure. RESULTS: The prevalence of menopausal symptoms (specifically hot flashes and night sweats) did not differ for exposed and unexposed women. One exposed woman and no unexposed women had a medically confirmed diagnosis of premature ovarian failure. CONCLUSIONS: Prenatal diethylstilbestrol exposure was not related to diagnosis or symptoms of rnenopause in this study. Further follow-up will be necessary to determine if a difference in age at rnenopause emerges as these women become older. (AM J OBSTET GYNECOL 1995;172:92-5.)
Key words:
Diethylstilbestrol,
menopause,
hot flashes, premature
Animal studies of prenatal exposure to diethylstilbestrol (DES) show toxic effects on the ovary. These effects include cystic ovaries, absence of corpora lutea, small ovaries, and abnormal ovarian histologic features.‘-’ Two studies have found fewer follicles in the ovaries of mice exposed prenatally.3, a In humans, ovarian toxins may decrease the number of ovarian follicles and produce an earlier-than-expected age at menolaause,9-‘3 No study of DES exposure in humans has addressed possible ovarian effects or age at menopause. \Jow that women who were exposed to DES prenatally are approaching menopausal age, this possible toxic effect of DES on the human ovary can be assessed. From 1950 to 1952, a double-blind randomized trial of DES in pregnancy was conducted at the Chicago Lying-In Hospital. Studies of female offspring from this trial have revealed a wide range of adverse effects of prenatal DES exposure, including benign abnormalities of reproductive tract epithelia, structural abnormalities From the Epidemiology Branch, Natzonal Institute of Environmental Health Sciences,” and the Department of Obstetrics and Gynecology, University of Chicago.’ Supported by the National Institute of Environmental Health Sciences (through intramural support and by contract support to the University of Chicago). Received for Publication A&l 4, 1994; revised May 31, 1994; accepted J”une*2 7, 1994. 1 Reprint requests: Paige P. Hornsby, PhD, Box 473 Health Sciences Center, University of Virginia, Charlottesville, VA 22908. 6/l/58725
92
ovarian
failure
of reproductive organs, infertility, and adverse pregnancy outcomes.“-‘* Daughters in this cohort are now approaching the age of 40. To assess a possible relationship between prenatal exposure to DES and ovarian toxicity, we asked questions about diagnosis and symptoms of menopause in the most recent follow-up study of these women. Material
and
methods
A total of 1646 pregnant women participated in the original randomized trial from 1950 through 1952. This study was double-blind and placebo controlled.‘9 The only criterion for enrollment was that the first prenatal visit occur before the 20th week of gestation. DES treatment was allocated to 840 women; the remainder received identical placebo tablets. The daily dose of DES increased through the thirty-fifth week of pregnancy, ranging from 5 to 150 mg, with total doses ranging from 10,325 to 12,477 mg among compliant participants. The mean dose was approximately 12,000 mg. Both medication and placebo tablets contained phenol red; compliance with the study protocol was monitored by checking for this dye in urine samples at each prenatal visit. Noncompliers were excluded from the study. A total of 1653 babies were born to women in the trial. Of 805 female births, 412 were exposed and 393 unexposed. The mothers and their offspring were traced and contacted > 20 years later, after the discovery of a link
Volume 172, Number Am J Obstet Gynecol
Table
1, Part
I. Characteristics
of study population
Race* White Black Other Education High school or vocational school Some college or 2 yr college College graduate Some graduate school or advanced degree Marital status Married or cohabiting Widowed, separated, or divorced Never married Employment status Employed Not employed Total family income* <$15,00O/yr $15,OOO/yr-$29,999/yr $30,OOO/yr-$44,999/yr 2 $45,00O/yr Smoking status Current Former Never Quetelet index <20 20-26 >26 Age at menarche <12yr 12-14 yr >14yr History of hysterectomy Yes No *Data
were
missing
for
Hornsby,
1
-
one or more
Exposed (n = 296) (%)
Unexposed (n = 246) (%)
91 4 4
90 6 3
19
17
24 24 32
27 24 32
77 13 10
77 14 9
76 24
70 30
6 15 22 54
4 20 24 49
20 28 52
17 32 52
9 66 25
8 68 24
22 68 9
23 67
4 96
5 95
11
participants.
between exposure and clear cell adenocarcinoma of the vagina among some DES daughters.” The female offspring have since been followed up for a variety of health outcomes, including cancer and reproductive function.‘4-‘s By 1990, 28 of the 805 original daughters were deceased (including infant deaths). We could not locate an additional 179 (80 exposed, 99 unexposed), leaving 598 (319 exposed, 279 unexposed) or 77% of the surviving cohort available for study. We carried out telephone interviews with 542 daughters (91% of those located), 296 exposed women and 246 unexposed women. Interviews lasted an average of 30 minutes and were conducted by trained interviewers who were blinded to the exposure status of the daughters. Participants answered questions about demographic, anthropometric, medical, reproductive, and menstrual variables, including diagnosis of premature ovarian failure (menopause before age 40) and symptoms of menopause, specifically hot flashes and night sweats.
Table II. Diagnosis of menopause
Wilcox,
and
Herbst
93
and symptoms Exposed (n ~~2,96’ 0
Medically confirmed diagnosis of premature ovarian failure Ever had night sweats Ever had hot flashes Ever had either hot flashes or night sweats
Unexposed (n = 246) (“ro) 0 18 19 27
We used x2 and Fisher’s exact tests of significance to compare the exposed and unexposed women on these outcome variables. Results Characteristics of the study population are presented in Table I. The exposed and unexposed women were similar with respect to a number of potentially confounding factors, including age (all were 37 to 39 years old), race, education, marital and employment status, income, smoking status, Quetelet index, age at menarche, and history of hysterectomy. The two groups of women differed somewhat with respect to reproductive and menstrual history (not shown). Exposed women had decreased gravidity and parity and increased risk of ectopic pregnancy, spontaneous abortion, preterm delivery, and stillbirth, as previously reported.‘” ” They were also more likely than the unexposed to report having sought medical evaluation for menstrual problems, specifically irregular cycles (33% of exposed women vs 20% of unexposed women), amenorrhea (20% vs 1 l%), and heavy or prolonged bleeding (15% vs 11%). However, exposed women were less likely than the unexposed to have sought medical evaluation for menopause (2% vs 3%). Table II presents the data regarding diagnosis and symptoms of menopause. On the basis of data from the interview alone, five exposed and no unexposed women reported a medical diagnosis of premature ovarian failure. We recontacted these women for permission to obtain medical records and were able to obtain relevant records for all five. In only one case was a diagnosis of premature ovarian failure confirmed. The exposed and unexposed women were very similar with respect to reported hot flashes and night sweats. This was true overall and also after we excluded women who had had a hysterectomy (11 exposed women and 13 unexposed). Among those who had ever experienced hot flashes or night sweats, a slight difference in age at onset of symptoms was found between the two groups (Table III). A higher proportion of exposed women reported onset before age 35, but this difference did not reach statistical significance (p = 0.23). Nearly identical proportions of exposed
94
Hornsby,
Wilcox,
and
Herbst
January Am J Obstet
Table III. Characteristics reported
of those who hot flashes or night sweats
-
-
Age at start of hot flashes or night sweats c35 yr 235yr Refused or don’t know Hot flashes or night sweats in last 3 mo
Exposed (n = 84) (%)
Cinexposed (n = 67) mi
38 54 8 57
28 61 10 58
and unexposed women reported experiencing either symptom in the last 3 months. This result was unchanged after we excluded women who were currently pregnant (n = 9), breast-feeding (n = 18), or taking exogenous hormones (n = 38). None of the slight differences in symptoms of menopause was statistically significant. Results were not altered by the exclusion of women with a history of thyroid problems or diagnosis of cancer (who might have received antineoplastic agents or chemotherapy that would affect ovarian function). Finally, we asked women if they had noticed changes in menstrual patterns in the 12 months before the interview. (Women who were currently pregnant, breast-feeding, or taking exogenous hormones or who had had a hysterectomy were excluded). Reported changes in amount of menstrual bleeding, duration of bleeding, and cycle length did not differ for the exposed and unexposed women. Comment DES is a synthetic estrogen that passes freely across the placenta to reach the fetus; its carcinogenic and teratogenic properties have been well documented in animals and in humans. DES has also been shown to be toxic to the ovary in animals. Similar effects in humans are biologically plausible, because human ovaries acquire all of their oocytes (approximately 6 million) by the fifth month of gestation. More than 99% of these oocytes are lost by a natural process of differentiation and atresia that begins in utero and continues into adulthood.” Reproductive toxins, and perhaps DES, may accelerate this process during fetal life, as well as thereafter. This is the first study to address a possible relationship between in utero exposure to DES and accelerated ovarian senescence as expressed by early menopause. We found a difference between exposed and unexposed women in self-reported diagnosis of premature ovarian failure, but this finding was not confirmed in medical records. Our finding of one medically dcoumented case is within the range of what would be expected on the
1995 Gym01
basis of data from a group of women followed up over time for assessment of age at natural menopause.‘3 The four exposed women who misreported a diagnosis of premature ovarian failure seem to have confused their diagnosis with other ovarian problems or conditions; three of the four women had actually been diagnosed with ovarian cysts. Cystic ovaries have not been addressed in prevous studies. We had not included questions about diagnosis of ovarian cysts, but we did ask about removal of ovarian cysts: 10% of exposed women versus 4% of unexposed women reported having had such a cyst removed. This possible effect of prenatal DES exposure deserves more thorough study. There were no differences between the exposed and unexposed in the two most common symptoms of menopause, hot flashes and night sweats. Although exposed daughters reported having their first menopausal symptoms at a younger age, this difference was not statistically significant and could be due to chance. Because this was a negative study, the issue of power deserves mention. Because of the low rate of occurrence of menopause in women < 40 years old, a study this size has adequate power only to detect a greatly increased risk (e.g., greater than fivefold) for exposed women. Symptoms of menopause are more common in women of this age group,“4 however, and may be an early indicator of menopasual onset. This study had >90% power to detect a doubling of risk of menopausal symptoms in the exposed. These data have at least two limitations: First, they are self-reported. We were able to obtain medical records to assess the accuracy of reported diagnosis of premature ovarian failure, but we have no indication of the validity of reported hot flahses and night sweats. There is little research on the accuracy of self-reported menopausal symptoms.24 If exposed women had reported more symptoms, we would have had to consider the possibility that their knowledge of their DES exposure sensitized them to their own medical conditions. However, with little or no difference in reported symptoms between exposed and unexposed women, the issue of biased reporting is moot. Furthermore, the proportion of women (both exposed and unexposed) who reported either hot flashes or night sweats was similar to what has been found in other populations of women in this age gro~p.“~ A second limitation of this study is that we did not ask reasons for hot flashes or night sweats. These symptoms can result from hormonal changes unrelated to menopause (for example, during or immediately after pregnancy or while breast-feeding). Forty-one women volunteered reasons other than menopause for why they thought they had experienced either symptom (e.g., pregnancy, breast-feeding, surgery, and prescription
Volume 172, Number Am J Obstet Gynecol
1, Part
Hornsby, Wilcox, and Herbst
1
drug use), and these reasons were distributed equally between the two groups. When we excluded women with symptoms whose reasons were other than menopause, the exposed and unexposed remained similar. Despite these limitations, this cohort provides a unique opportunity to study the effects of prenatal DES exposure because allocation of DES was experimentally controlled. The exposed and unexposed daughters are therefore comparable with respect to many potentially confounding factors. In our study of women aged 37 to 39, there appears to be no relationship between prenatal DES exposure and diagnosis or symptoms of early menopause. A small difference in self-reported diagnosis of premature ovarian failure was not confirmed in medical records. Further follow-up of this cohort and other groups of DES-exposed women as they enter menopausal age may provide more complete information about possible DES effects on menopause, as well as other late health effects from this powerful prenatal drug.
8.
9.
10. 11.
12. 13.
14.
15.
16.
We acknowledge the contributions of Joy Pierce, Donna Baird, Clarice Weinberg, and Sioban Harlow. 17. REFERENCES
1.
Rustia M, Shubik P. Transplacental effects of diethylstilbestrol on the genital tract of hamster offspring. Cancer
Lett 1976;1:139-46. JA, Newbold RR, Bullock BD. Long-term ef2. McLachlan fects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res 1980; 40:3988-99. 3. Haney AF, Newbold RR, McLachlan JA. Prenatal diethylstilbestrol exposure in the mouse: effects on ovarian histology and steroidogenesis in vitro. Biol Reprod 1984;30; 471-8. 4. Henry EC, Miller RK, Baggs RB. Direct fetal injections of diethylstilbestrol and estradiol: a method for investigating their’teratogenicity. Teratology 1984;29:297-304. 5. Hines M, Gov RW. Estrogen before birth and develonment of sex-related reproduc&e traits in the female guinea pig. Horm Behav 1985;19:331-47. 6. Iguchi T, Takasugi N. Polyovular follicles in the ovary of immature mice exposed prenatally to diethylstilbestrol. Anat Embryo1 1986;175:53-5. 7. Hines M, Alsum P, Roy M, Gorski RA, Goy RW. Estrogenic contributions to sexual differentiation in the female I
1
18.
19.
20.
21.
guinea pig: influences of diethylstilbestrol and tamoxifen on neural, behavioral, and ovarian development. Horm Behav 1987;21:402-17. McLachlan JA, Newbold RR, Shah HC, Hogan MD, Dixon RL. Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertil Steril 1982;38:36471. Sobrinho LG, Levine RA, DeConti RC. Amenorrhea in patients with Hodgkin’s disease treated with antineoplastic agents. AM J O&T GYNECOL 1971;109:135-9. 1 Uldall PR. Kerr DNS. Tacchi D. Sterilitv and cvcloohosphamide. Lancet 1972;1:693-4. ’ ’ ’ Warne GL, Fairley KF, Hobbs JB. Martin FIR. Cyclophosphamide-induced ovarian failure. N Engl J Med 1973;289: 1159-62. Chapman RM. Gonadal injury resulting from chemotherapy. Am J Ind Med 1983;4:149-61. Mattison DR. Clinical manifestations of ovarian toxicity. In: Dixon RL, ed. Reproductive toxicology. New York: Raven Press, 1985: 109-30. Bibbo M, Gill WB, Azizi F, et al. Follow-up study of male and female offspring of DES-exposed mothers. Obstet Gynecol 1977;49:1-8. Herbst AL, Hubby MM, Blough RR, Azizi F. A comparison of pregnancy experience in DES-exposed and DES-unexposed daughters. J Reprod Med 1980;24:62-9. Herbst AL, Hubby MM, Azizi F, Makii MM. Reproductive and gynecologic surgical experience in diethylstilbestrolexposed daughters. AM J OBSTET GYNECOL 1981;141:101928. Senekjian EK, Potkul RK, Frey K, Herbst AL. Infertility among daughters either exposed or not exposed to dietiylstilb&trolyAM J OBSTET ~YNECOL 1988;1<8:493-8. Herbst AL, Senekiian EK, Frev K. Abortion and nreznancv loss among dieth;lstilbe&ol-kxposed women. ien& R& prod Endocrinol 1989;7:124-9. Dieckmann WJ, Davis ME, Rynkiewicz LM, Pottinger RE. Does the administration of diethylstilbestrol during pregnancy have therapeutic value? AM J OBSTET GWECOL 1953; 66:1062-81. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina: association of maternal stilbesterol therapy with tumor appearance in young women. N Engl J Mkh 1971;284:878-81. Barnes AB, Colton T, Gundersen 1, et al. Fertilitv and outcome of pregnancy in women “exposed in u&o to diethvlstilbestrol. N Engl I Med 1980:302:609-13. Speroff L, Glass RH, Kase NG. Clinical gynecologic endocrinology and infertility. 3rd ed. Baltimore: Williams & Wilkins, 1983:102. Treloar AE. Menstrual cyclicity and the pre-menopause. Maturitas 1981;3:249-64. Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci 1990;592:52-86. ”
22.
23. 24.
95
LI
Onset of menopause in women exposed to diethylstilbestrol in utero Paige P. Hornsby, Research Triangle
PhD,” Allen J. Wilcox, Park, North Carolina,
MD, PhD,” and Arthur
and Chicago,
L. Herb&,
MD’
Illinois
OBJECTIVES: As part of a larger health survey, we sought to determine whether prenatal exposure to diethylstilbestrol is associated with onset of early menopause or menopausal symptoms. STUDY DESIGN: Diagnosis of premature ovarian failure and symptoms of menopause were determined in a telephone interview with 542 women whose mothers participated in a randomized clinical trial of the use of diethylstilbestrol in pregnancy in the early 1950-s. These women were aged 37 to 39 at the time of the interview. Medical records were obtained to confirm diagnosis of premature ovarian failure. RESULTS: The prevalence of menopausal symptoms (specifically hot flashes and night sweats) did not differ for exposed and unexposed women. One exposed woman and no unexposed women had a medically confirmed diagnosis of premature ovarian failure. CONCLUSIONS: Prenatal diethylstilbestrol exposure was not related to diagnosis or symptoms of rnenopause in this study. Further follow-up will be necessary to determine if a difference in age at rnenopause emerges as these women become older. (AM J OBSTET GYNECOL 1995;172:92-5.)
Key words:
Diethylstilbestrol,
menopause,
hot flashes, premature
Animal studies of prenatal exposure to diethylstilbestrol (DES) show toxic effects on the ovary. These effects include cystic ovaries, absence of corpora lutea, small ovaries, and abnormal ovarian histologic features.‘-’ Two studies have found fewer follicles in the ovaries of mice exposed prenatally.3, a In humans, ovarian toxins may decrease the number of ovarian follicles and produce an earlier-than-expected age at menolaause,9-‘3 No study of DES exposure in humans has addressed possible ovarian effects or age at menopause. \Jow that women who were exposed to DES prenatally are approaching menopausal age, this possible toxic effect of DES on the human ovary can be assessed. From 1950 to 1952, a double-blind randomized trial of DES in pregnancy was conducted at the Chicago Lying-In Hospital. Studies of female offspring from this trial have revealed a wide range of adverse effects of prenatal DES exposure, including benign abnormalities of reproductive tract epithelia, structural abnormalities From the Epidemiology Branch, Natzonal Institute of Environmental Health Sciences,” and the Department of Obstetrics and Gynecology, University of Chicago.’ Supported by the National Institute of Environmental Health Sciences (through intramural support and by contract support to the University of Chicago). Received for Publication A&l 4, 1994; revised May 31, 1994; accepted J”une*2 7, 1994. 1 Reprint requests: Paige P. Hornsby, PhD, Box 473 Health Sciences Center, University of Virginia, Charlottesville, VA 22908. 6/l/58725
92
ovarian
failure
of reproductive organs, infertility, and adverse pregnancy outcomes.“-‘* Daughters in this cohort are now approaching the age of 40. To assess a possible relationship between prenatal exposure to DES and ovarian toxicity, we asked questions about diagnosis and symptoms of menopause in the most recent follow-up study of these women. Material
and
methods
A total of 1646 pregnant women participated in the original randomized trial from 1950 through 1952. This study was double-blind and placebo controlled.‘9 The only criterion for enrollment was that the first prenatal visit occur before the 20th week of gestation. DES treatment was allocated to 840 women; the remainder received identical placebo tablets. The daily dose of DES increased through the thirty-fifth week of pregnancy, ranging from 5 to 150 mg, with total doses ranging from 10,325 to 12,477 mg among compliant participants. The mean dose was approximately 12,000 mg. Both medication and placebo tablets contained phenol red; compliance with the study protocol was monitored by checking for this dye in urine samples at each prenatal visit. Noncompliers were excluded from the study. A total of 1653 babies were born to women in the trial. Of 805 female births, 412 were exposed and 393 unexposed. The mothers and their offspring were traced and contacted > 20 years later, after the discovery of a link
Volume 172, Number Am J Obstet Gynecol
Table
1, Part
I. Characteristics
of study population
Race* White Black Other Education High school or vocational school Some college or 2 yr college College graduate Some graduate school or advanced degree Marital status Married or cohabiting Widowed, separated, or divorced Never married Employment status Employed Not employed Total family income* <$15,00O/yr $15,OOO/yr-$29,999/yr $30,OOO/yr-$44,999/yr 2 $45,00O/yr Smoking status Current Former Never Quetelet index <20 20-26 >26 Age at menarche <12yr 12-14 yr >14yr History of hysterectomy Yes No *Data
were
missing
for
Hornsby,
1
-
one or more
Exposed (n = 296) (%)
Unexposed (n = 246) (%)
91 4 4
90 6 3
19
17
24 24 32
27 24 32
77 13 10
77 14 9
76 24
70 30
6 15 22 54
4 20 24 49
20 28 52
17 32 52
9 66 25
8 68 24
22 68 9
23 67
4 96
5 95
11
participants.
between exposure and clear cell adenocarcinoma of the vagina among some DES daughters.” The female offspring have since been followed up for a variety of health outcomes, including cancer and reproductive function.‘4-‘s By 1990, 28 of the 805 original daughters were deceased (including infant deaths). We could not locate an additional 179 (80 exposed, 99 unexposed), leaving 598 (319 exposed, 279 unexposed) or 77% of the surviving cohort available for study. We carried out telephone interviews with 542 daughters (91% of those located), 296 exposed women and 246 unexposed women. Interviews lasted an average of 30 minutes and were conducted by trained interviewers who were blinded to the exposure status of the daughters. Participants answered questions about demographic, anthropometric, medical, reproductive, and menstrual variables, including diagnosis of premature ovarian failure (menopause before age 40) and symptoms of menopause, specifically hot flashes and night sweats.
Table II. Diagnosis of menopause
Wilcox,
and
Herbst
93
and symptoms Exposed (n ~~2,96’ 0
Medically confirmed diagnosis of premature ovarian failure Ever had night sweats Ever had hot flashes Ever had either hot flashes or night sweats
Unexposed (n = 246) (“ro) 0 18 19 27
We used x2 and Fisher’s exact tests of significance to compare the exposed and unexposed women on these outcome variables. Results Characteristics of the study population are presented in Table I. The exposed and unexposed women were similar with respect to a number of potentially confounding factors, including age (all were 37 to 39 years old), race, education, marital and employment status, income, smoking status, Quetelet index, age at menarche, and history of hysterectomy. The two groups of women differed somewhat with respect to reproductive and menstrual history (not shown). Exposed women had decreased gravidity and parity and increased risk of ectopic pregnancy, spontaneous abortion, preterm delivery, and stillbirth, as previously reported.‘” ” They were also more likely than the unexposed to report having sought medical evaluation for menstrual problems, specifically irregular cycles (33% of exposed women vs 20% of unexposed women), amenorrhea (20% vs 1 l%), and heavy or prolonged bleeding (15% vs 11%). However, exposed women were less likely than the unexposed to have sought medical evaluation for menopause (2% vs 3%). Table II presents the data regarding diagnosis and symptoms of menopause. On the basis of data from the interview alone, five exposed and no unexposed women reported a medical diagnosis of premature ovarian failure. We recontacted these women for permission to obtain medical records and were able to obtain relevant records for all five. In only one case was a diagnosis of premature ovarian failure confirmed. The exposed and unexposed women were very similar with respect to reported hot flashes and night sweats. This was true overall and also after we excluded women who had had a hysterectomy (11 exposed women and 13 unexposed). Among those who had ever experienced hot flashes or night sweats, a slight difference in age at onset of symptoms was found between the two groups (Table III). A higher proportion of exposed women reported onset before age 35, but this difference did not reach statistical significance (p = 0.23). Nearly identical proportions of exposed
94
Hornsby,
Wilcox,
and
Herbst
January Am J Obstet
Table III. Characteristics reported
of those who hot flashes or night sweats
-
-
Age at start of hot flashes or night sweats c35 yr 235yr Refused or don’t know Hot flashes or night sweats in last 3 mo
Exposed (n = 84) (%)
Cinexposed (n = 67) mi
38 54 8 57
28 61 10 58
and unexposed women reported experiencing either symptom in the last 3 months. This result was unchanged after we excluded women who were currently pregnant (n = 9), breast-feeding (n = 18), or taking exogenous hormones (n = 38). None of the slight differences in symptoms of menopause was statistically significant. Results were not altered by the exclusion of women with a history of thyroid problems or diagnosis of cancer (who might have received antineoplastic agents or chemotherapy that would affect ovarian function). Finally, we asked women if they had noticed changes in menstrual patterns in the 12 months before the interview. (Women who were currently pregnant, breast-feeding, or taking exogenous hormones or who had had a hysterectomy were excluded). Reported changes in amount of menstrual bleeding, duration of bleeding, and cycle length did not differ for the exposed and unexposed women. Comment DES is a synthetic estrogen that passes freely across the placenta to reach the fetus; its carcinogenic and teratogenic properties have been well documented in animals and in humans. DES has also been shown to be toxic to the ovary in animals. Similar effects in humans are biologically plausible, because human ovaries acquire all of their oocytes (approximately 6 million) by the fifth month of gestation. More than 99% of these oocytes are lost by a natural process of differentiation and atresia that begins in utero and continues into adulthood.” Reproductive toxins, and perhaps DES, may accelerate this process during fetal life, as well as thereafter. This is the first study to address a possible relationship between in utero exposure to DES and accelerated ovarian senescence as expressed by early menopause. We found a difference between exposed and unexposed women in self-reported diagnosis of premature ovarian failure, but this finding was not confirmed in medical records. Our finding of one medically dcoumented case is within the range of what would be expected on the
1995 Gym01
basis of data from a group of women followed up over time for assessment of age at natural menopause.‘3 The four exposed women who misreported a diagnosis of premature ovarian failure seem to have confused their diagnosis with other ovarian problems or conditions; three of the four women had actually been diagnosed with ovarian cysts. Cystic ovaries have not been addressed in prevous studies. We had not included questions about diagnosis of ovarian cysts, but we did ask about removal of ovarian cysts: 10% of exposed women versus 4% of unexposed women reported having had such a cyst removed. This possible effect of prenatal DES exposure deserves more thorough study. There were no differences between the exposed and unexposed in the two most common symptoms of menopause, hot flashes and night sweats. Although exposed daughters reported having their first menopausal symptoms at a younger age, this difference was not statistically significant and could be due to chance. Because this was a negative study, the issue of power deserves mention. Because of the low rate of occurrence of menopause in women < 40 years old, a study this size has adequate power only to detect a greatly increased risk (e.g., greater than fivefold) for exposed women. Symptoms of menopause are more common in women of this age group,“4 however, and may be an early indicator of menopasual onset. This study had >90% power to detect a doubling of risk of menopausal symptoms in the exposed. These data have at least two limitations: First, they are self-reported. We were able to obtain medical records to assess the accuracy of reported diagnosis of premature ovarian failure, but we have no indication of the validity of reported hot flahses and night sweats. There is little research on the accuracy of self-reported menopausal symptoms.24 If exposed women had reported more symptoms, we would have had to consider the possibility that their knowledge of their DES exposure sensitized them to their own medical conditions. However, with little or no difference in reported symptoms between exposed and unexposed women, the issue of biased reporting is moot. Furthermore, the proportion of women (both exposed and unexposed) who reported either hot flashes or night sweats was similar to what has been found in other populations of women in this age gro~p.“~ A second limitation of this study is that we did not ask reasons for hot flashes or night sweats. These symptoms can result from hormonal changes unrelated to menopause (for example, during or immediately after pregnancy or while breast-feeding). Forty-one women volunteered reasons other than menopause for why they thought they had experienced either symptom (e.g., pregnancy, breast-feeding, surgery, and prescription
Volume 172, Number Am J Obstet Gynecol
1, Part
Hornsby, Wilcox, and Herbst
1
drug use), and these reasons were distributed equally between the two groups. When we excluded women with symptoms whose reasons were other than menopause, the exposed and unexposed remained similar. Despite these limitations, this cohort provides a unique opportunity to study the effects of prenatal DES exposure because allocation of DES was experimentally controlled. The exposed and unexposed daughters are therefore comparable with respect to many potentially confounding factors. In our study of women aged 37 to 39, there appears to be no relationship between prenatal DES exposure and diagnosis or symptoms of early menopause. A small difference in self-reported diagnosis of premature ovarian failure was not confirmed in medical records. Further follow-up of this cohort and other groups of DES-exposed women as they enter menopausal age may provide more complete information about possible DES effects on menopause, as well as other late health effects from this powerful prenatal drug.
8.
9.
10. 11.
12. 13.
14.
15.
16.
We acknowledge the contributions of Joy Pierce, Donna Baird, Clarice Weinberg, and Sioban Harlow. 17. REFERENCES
1.
Rustia M, Shubik P. Transplacental effects of diethylstilbestrol on the genital tract of hamster offspring. Cancer
Lett 1976;1:139-46. JA, Newbold RR, Bullock BD. Long-term ef2. McLachlan fects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res 1980; 40:3988-99. 3. Haney AF, Newbold RR, McLachlan JA. Prenatal diethylstilbestrol exposure in the mouse: effects on ovarian histology and steroidogenesis in vitro. Biol Reprod 1984;30; 471-8. 4. Henry EC, Miller RK, Baggs RB. Direct fetal injections of diethylstilbestrol and estradiol: a method for investigating their’teratogenicity. Teratology 1984;29:297-304. 5. Hines M, Gov RW. Estrogen before birth and develonment of sex-related reproduc&e traits in the female guinea pig. Horm Behav 1985;19:331-47. 6. Iguchi T, Takasugi N. Polyovular follicles in the ovary of immature mice exposed prenatally to diethylstilbestrol. Anat Embryo1 1986;175:53-5. 7. Hines M, Alsum P, Roy M, Gorski RA, Goy RW. Estrogenic contributions to sexual differentiation in the female I
1
18.
19.
20.
21.
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