RADIATION RESEARCH 176, 787–795 (2011)0033-7587/11 $15.00
Ó2011 by Radiation Research Society.
All rights of reproduction in any form reserved.
DOI: 10.1667/RR2676.1

Effect of Radiation on Age at Menopause among Atomic Bomb Survivors
Ritsu Sakata,1 Yukiko Shimizu, Midori Soda, Michiko Yamada, Wan-Ling Hsu, Mikiko Hayashi and Kotaro Ozasa
Radiation Effects Research Foundation, Hiroshima and Nagasaki, JapanINTRODUCTION
Sakata, R., Shimizu, Y., Soda, M., Yamada, M., Hsu, W-L.,
Hayashi, M., Ozasa, K. Effect of Radiation on Age at
Menopause among Atomic Bomb Survivors. Radiat. Res.
176, 787–795 (2011).

Exposure to ionizing radiation has been thought to induce
ovarian failure and premature menopause based on thefollow-up of female patients who underwent radiotherapy (1–5). Since most of those effects were observed in patients withhigh-dose radiotherapy, the effects of low-dose radiation are
still unclear. The atomic bomb (A-bomb) survivors were
exposed to relatively low doses of radiation compared tothose in the radiotherapy studies. An early study showed thatthe proportion of female A-bomb survivors who experienced
menopause immediately after the exposure was significantly
larger in the proximal exposure group compared to the distal
exposure group, with average menopausal age being
significantly younger, particularly among those with acuteradiation syndromes (6). However, it remains speculative
whether the younger menopausal age is caused by physicalinjury or psychological trauma due to their experiences in thebombing and bad health conditions after that or by effects ofradiation on ovarian function.
Menopause is classified as either natural or artificial. The
former is caused by spontaneous loss of ovarian function.
Early natural menopause has been associated with increased
risks of osteoporosis (7) and cardiovascular diseases (8) as
well as with a higher mortality from all causes (9). Thus
early natural menopause serves as an additional health risk
among elderly females. Artificial menopause is caused
mainly by artificial loss of ovarian function by bilateraloophorectomy and hysterectomy with unilateral oophorectomy and sometimes by intensive radiotherapy andchemotherapy against cancers of the uterus and ovary (10).
Investigation of the association of exposure to A-bombradiation and early natural menopause that occurred longafter the exposure is important to evaluate the late healtheffects of radiation exposure on ovarian function at
relatively low dose levels compared with those afterradiotherapy. It is also important to investigate artificial
menopause in the female A-bomb survivors because ovarianand uterine corpus cancers have increased among them (11)and often lead to oophorectomy and abdominal radiation
therapy and the induction of artificial menopause. Investigations limited to natural menopause were thought tounderestimate the overall effects of A-bomb radiation on
menopause. Therefore, we investigated the age at naturaland artificial menopause occurring at least 5 years after the

Exposure to ionizing radiation has been thought to induce
ovarian failure and premature menopause. Proximally
exposed female atomic bomb survivors were reported toexperience menopause immediately after the exposure more
often than those who were distally exposed. However, itremains unclear whether such effects were caused by physicalinjury and psychological trauma or by direct effects ofradiation on the ovaries. The objective of this study was to see
if there are any late health effects associated with theexposure to atomic bomb radiation in terms of age atmenopause in a cohort of 21,259 Life Span Study female Abomb survivors. Excess absolute rates (EAR) of natural andartificial menopause were estimated using Poisson regression.
A linear threshold model with a knot at 0.40 Gy [95%confidence interval (CI): 0.13, 0.62] was the best fit for a dose
response of natural menopause (EAR at 1 Gy at age of 50
years ¼ 19.4/1,000 person-years, 95% CI: 10.4, 30.8) and alinear threshold model with a knot at 0.22 Gy (95% CI: 0.14,0.34) was the best fit for artificial menopause (EAR at 1 Gy at
age of 50 years for females who were exposed at age of 20
years ¼ 14.5/1,000 person-years, 95% CI: 10.2, 20.1). Effectmodification by attained age indicated that EARs peakedaround 50 years of age for both natural and artificial
menopause. Although effect modification by age at exposure
was not significant for natural menopause, the EAR for
artificial menopause tended to be larger in females exposed atyoung ages. On the cumulative incidence curve of natural
menopause, the median age at menopause was 0.3 years
younger in females exposed to radiation of 1 Gy comparedwith unexposed females. The median age was 1 year younger
for combined natural and artificial menopause in the same
comparison. In conclusion, age at menopause was thought todecrease with increasing radiation dose for both natural andartificial menopause occurring at least 5 years after the
exposure. Ó 2011 by Radiation Research Society

1 Address for correspondence: Department of Epidemiology,
Radiation Effects Research Foundation, 5-2 Hijiyama Koen, Minami-ku, Hiroshima, Japan 732-0815; e-mail: rsakata@rerf.or.jp.

787

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SAKATA ET AL.

FIG. 1. Breakdown of the study population.

radiation exposure in the Life Span Study (LSS) populationof the Radiation Effects Research Foundation (RERF).
SUBJECTS AND METHODS

Study Population

The LSS is a longitudinal cohort study consisting of
50,175 males and 70,146 females who either were exposedto the atomic bombings in Hiroshima or Nagasaki or were
nonexposed (Fig. 1). Follow-up of the cohort was initiatedin 1950 by the Atomic Bomb Casualty Commission andthen carried on by RERF (12). RERF conducted three mailsurveys (1969, 1978 and 1991) on the female subjects in the
LSS population. Among 50,958 females with known
radiation dose in the LSS, 26,290 subjects replied to thequestion about menopause in one of the three surveys. In the
mail survey questionnaires, age at menopause was asked
about in the following manner without any detailed
information (underlined blanks to be filled in with age
information): ‘‘Age at menopause was _____ years’’ in the1969 mail survey, and ‘‘How old were you when yourmenstrual periods stopped? ______ years of age’’ in the1978 and 1991 mail surveys. The subject’s age atmenopause was determined by the reply to the question
about age at menopause in the earliest mail survey. The
subjects reporting that they had not experienced menopause
in the latest mail survey were treated as censored subjects attheir ages at that time. In the 1978 and 1991 surveys, thequestionnaires asked about menopause separately by natural
or artificial category, but this was not asked in the 1969survey. Cessation of menses caused by hysterectomy is notmenopause by medical definition if ovarian function
remains. However, most people assume cessation of menses
is menopause regardless of cause. Since detailed information on the cause of menopause was not obtained in thequestionnaires, we defined cessation of menses after
hysterectomy and other gynecological surgeries as artificial
menopause.
The population at risk in this study was the female LSS
subjects who were between 30 and 60 years of age and did
not experience menopause because this age range isassumed to include the potential for menopause. The
subjects who reported the following were excluded fromthe analysis: (1) onset of menopause before the A-bomb
exposure (1,559 subjects); (2) age at menopause of 30 years
or younger or of 60 years or older (133 subjects); (3) those
who reported menopause status only in the mail survey

789

AGE AT MENOPAUSE AMONG ATOMIC BOMB SURVIVORSTABLE 1
Number of Female Subjects Included in This Study from theLife Span Study (LSS) Cohort by City and Dose Categories
Weightedovariandose (Gy)

Hiroshima (%a)

Nagasaki (%a),0.005
0.005, ,0.5
0.5, ,1.0
1.0, ,1.5
1.5
Total

5,624 (43)8,494 (44)483 (36)133 (32)110 (28)
14,844 (43)3,602 (37)2,432 (43)241 (40)
87 (36)53 (36)
6,415 (39)

Subjects of this study

one of the three surveys. Age at menarche was determinedas the age at menarche informed by the earliest available
survey. Ever-smoker was defined as the subject who was asmoker or ex-smoker at the mail survey that determined her
age at menopause, and nonsmoker was defined in the samemanner. For censored subjects, smoking status wasdetermined by the latest available survey. When any
information was not available for parity, age at menarche,or smoking, the value was treated as missing.
Statistical AnalysisaPercentage of females in the whole LSS cohort by city and dose
categories.

before the age of 30 and did not respond to subsequent mailsurveys (242 subjects); and (4) inconsistent replies, e.g.,natural menopause with history of uterine or ovarian cancer,
or premenopausal status when older than 60 at the time of
the mail survey (1,771 subjects). In addition, the subjects
who experienced menopause within 5 years after A-bomb
exposure were excluded from the analyses in an effort to
exclude the potential effects of physical injury andpsychological trauma after A-bomb exposure (1,326
subjects). Consequently, the study population consisted of
21,259 females, 42% of the target population. The
distribution of the subjects by city and dose category is
shown in Table 1.
Subjects were included in the observation at age 30 years
and reached the end point at age of menopause (for bothnatural and artificial) or were treated as censored at age at
the latest mail survey that reported premenopausal status(the age had to be younger than 60 years due to the
exclusion criteria). If a subject reported being premenopausal in a specific mail survey and did not report the age ofmenopause in the later mail surveys, she was treated as
censored at the age at the specific mail survey. In theanalysis for natural menopause, subjects who experienced
artificial menopause were treated as censored at the age ofartificial menopause, and in the analysis for artificial
menopause, subjects who experienced natural menopause
were censored in the same way at that age.
Radiation and Other Risk Factors

Radiation doses for the ovary have been estimated basedon information regarding individual location and shielding
status at the time of the bombings in terms of c-ray dose andneutron dose using the Dosimetry System 2002 (DS02)(13). Individual weighted ovarian doses were calculated as
the sum of c-ray dose plus 10 times the neutron dose.
Information on parity, smoking status and age at
menarche was obtained from the mail surveys. Parity was
categorized as parous and nulliparous; the former was
defined as experience of delivery based on the replies to thequestions about age at first delivery, number of children,
number of deliveries, and other relevant information in any

Poisson regression was used to estimate the excess
absolute rates (EAR) for onset of menopause associatedwith weighted ovarian dose (d) effects. EAR indicates thenumber of excess outcomes per unit person-years and isthought to be the most appropriate measure of risk because
background rates for menopause are very irregular with theattained age, i.e., extremely high at nearly 50 years of age.
The EAR model we used was
k0 ðc; b; p; s; m; aÞ þ qðdÞeða; eÞ;
where the variables are city (c), birth year (b), parity (p),smoking status (s), age at menarche (m), attained age (a),radiation dose (d) and age at exposure (e) (14).
The function of k0(c,b,p,s,m,a) described the backgroundincidence rate of menopause. We considered interaction
between attained age and other factors in the backgroundrate function. The function q(d) represents dose response.
The following dose–response models were compared formodel fit:qðdÞ ¼ bd
qðdÞ ¼ bd þ cd2
qðdÞ ¼ cd2
bðd  sÞ d . s
0Linear ðLÞ
Linear-quadratic ðLQÞQuadratic ðQÞ

d.s
ds

Linear threshold ðLTÞs is a threshold dose, which was examined for a wide rangeof possible values by stepping up by 0.01 Gy. The functionof e(a,e) was assumed as effect modification on EAR byattained age (a) and age at exposure (e). First, the bestfitting function was determined among the four models, andsignificance of effect modification by attained age and age
at exposure was tested on the selected model. After that thebest-fitting model was determined again among the fourmodels with the effect modification term. We used the
Akaike Information Criteria (AIC) for comparison of model
fitting. Significance tests of improvement in model fit
between nested models were based on likelihood ratio tests.
Onset of menopause and time at risk in terms of personyears were tabulated by age at exposure (5-year categories
for ages 0 through 39 and 40 or higher), attained age (5-year
intervals for ages 30 through 60), birth cohort (10 categories
with 5-year intervals for 1894 through 1939 and 1940 or

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SAKATA ET AL.

TABLE 2Distribution of Subjects and Mean Age at Menopause by Available Covariates
Natural menopause
Categories
City
Hiroshima
Nagasaki
Birth cohort
1894–1905
1906–1925
1926–1945
ParityParousNulliparous
Missing
Smoking status
Never smoker
Ever smoker
Missing
Age at menarche,515, 16.17
Missing
Total

Artificial menopause

Censored

na

Ageb

Pc

na

Ageb

Pc

na

Total

11,657
4,864

49.5
49.5

0.80

1,661
747

43.7
43.2

0.02

1,526
804

14,844
6,415

1,105
9,056
6,360

50.9
49.3
49.6

,0.001

19
857
1,532

50.5
44.5
43.0

,0.001

0
51
2,279

1,124
9,964
10,171

14,078
1,362
1,081

49.6
49.1
49.3

,0.001

1,934
285
189

43.8
42.7
42.6

,0.001

2,035
160
135

18,047
1,807
1,405

13,206
2,820
495

49.7
49.0
49.5

,0.01

1,888
482
38

43.7
43.1
44.1

0.06

1,954
342
34

17,048
3,644
567

5,296
5,351
2,507
3,367
16,521

49.6
49.5
49.5
49.6
(78%)

0.57

977
708
261
462
2,408

43.6
43.8
43.3
43.3
(11%)

0.18

1,220
432
91
587
2,330

7,493
6,491
2,859
4,416
21,259(11%)

aNumber of females.
Mean age at menopause.
c
P for test of independence.
b

later), radiation dose (0.005, 0.02, 0.04, 0.06, 0.08, 0.1,
0.125, 0.15, 0.175, 0.2, 0.25, 0.3, 0.5, 0.75, 1.0, 1.25, 1.5,
1.75, 2.0, 2.5 and 3 Gy), city (Hiroshima and Nagasaki),parity (parous, nulliparous and missing), smoking history(never, ever and missing), and age at menarche (age 14 oryounger, 15 or 16, 17 or older, and missing). The cellspecific mean values are also included for radiation doseand each age/time variable. Statistical analyses were carriedout using the AMFIT program of Epicure software (15).
Cumulative Incidence Curves of Menopause

Cumulative incidence curves of menopause were illustrated based on the best-fitting models. The incidence rate ofcombined natural and artificial menopause at a given age
was the sum of them, each of which was calculated
separately based on the best-fitting model. The numbers offemales who were expected to reach menopause at a given
age were calculated by multiplying the number ofpremenopausal subjects by the incidence rate of menopause
at that age. Then the cumulative incidence of menopause
was estimated under the condition of being exposed in
Hiroshima, born in 1925, parous, experiencing menarche atage 15 or 16 years, and never smoking.
RESULTS

Among the eligible of 21,259 subjects, 16,521 reported
that they had experienced natural menopause and 2,408

reported artificial menopause. The other 2,330 subjects were
censored. Mean ages of menopause by background factor
are shown in Table 2. Natural menopause was experienced
at younger ages in the subjects who had not experienced
childbirth compared with those who had (P , 0.001). It wasalso experienced at younger ages in ever-smokers comparedwith never-smokers (P , 0.01). However, the mean age atnatural menopause was not significantly different between
the cities and categories of age at menarche. Similartendencies were observed for artificial menopause, though
artificial menopause was experienced at younger ages thannatural menopause.
Table 3 shows the mean age at menopause by weighted
ovarian dose. Mean age at natural menopause for the
subjects with the dose range of 0.005–0.5 Gy appeared to be
similar to those with doses under 0.005 Gy and became
younger with increasing radiation dose over 0.5 Gy. Meanage at artificial menopause also decreased with increasing
dose. Proportions of artificial menopause in the total
menopause in a given dose range markedly increased at
0.5 Gy or higher, reaching 40% among the subjects who
were exposed to a dose of 1.5 Gy or higher.
The distribution of females who experienced natural
menopause before age 45 by weighted ovarian dose isshown in Table 4. In the lowest dose category, 7% of females
experienced menopause before age 45, the percentage
increased with dose, and 19% of females experienced
menopause before age 45 in the highest dose category in

791

AGE AT MENOPAUSE AMONG ATOMIC BOMB SURVIVORSTABLE 3
Mean Age at Menopause by Weighted Ovarian Dose Categories
Weightedovariandose (Gy)N,0.005
0.005, ,0.5
0.5, ,1.0
1.0, ,1.5
1.5
Total

Natural menopause
a

b

(% )

9,226
10,926
724
220
163

7,231
8,475
561
156
98

(88)
(88)
(82)
(77)
(60)

21,25916,521(87)ncArtificial menopausedMean age

b

n

(%c)

Mean aged

49.6 6 3.4
49.5 6 3.4
49.2 6 3.3
48.9 6 3.7
47.9 6 4.2
Pe , 0.0001
49.5 6 3.4

972
1,204
120
47
65

(12)
(12)
(18)
(23)
(40)

2,408

(13)

43.7 6 5.1
43.6 6 5.3
42.9 6 4.8
42.7 6 5.7
41.7 6 5.2
Pe ¼ 0.0135
43.6 6 5.2

aNumber of females by dose category including censored females.
Number of females experiencing natural (or artificial) menopause by dose category.
cPercentage experiencing natural (or artificial) menopause in total menopause.
dMean age at menopause.
e
P for trend.
bwhich females received 1.5 Gy or more (mean dose 2 Gy).
The probability of experiencing natural menopause before
age 45 increased significantly with dose (P , 0.001).
Table 5 shows results of Poisson regression analysis.
Since birth cohort, parity, smoking status and age at
menarche had significant interactions with attained age inthe background rate function [k0(c,b,p,s,m,a)], thoseinteraction terms were included in the function of themodel for natural menopause as well as main effects.
For natural menopause, the LT model with effectmodification by attained age was the model with the bestfit (EAR at 1 Gy at age of 50 years ¼ 19.4/1,000 personyears, 95% CI: 10.4, 30.8). The threshold was estimated tobe 0.40 Gy (95% CI: 0.13, 0.62). EAR for natural
menopause peaked at 50 years of age, which was expressedby a significant effect modification by attained age [ln(age/50)2, P , 0.001]. The effect modification by age at
exposure was not statistically significant (P ¼ 0.19). The
shape of the dose response and EAR estimates for
categorized dose are shown in Fig. 2. The model ultimately
selected for natural menopause was
TABLE 4
Distribution of Natural Menopause Experienced before Age
45 by Ovarian Dose Categories
Age at natural menopause
Weightedovariandose (Gy)

Mean dose(Gy),45 years

45 years

na

(%b)

na

,0.005
0.005, ,0.5
0.5, ,1.0
1.0, ,1.5
1.5

0.001
0.088
0.689
1.222
1.972

477
584
43
18
19

Total

0.092

1,141

6.6
6,754
6.9
7,891
7.7
518
11.5
138
19.4
79
Pc , 0.001
15,380a

Number of females.
Percentage of females in natural menopause.
c
P for the Cochran-Armitage test.
b

(%b)
93.4
93.1
92.3
88.5
80.6

k0 ðc; b; 
p; s; m; aÞ þ 32:3td exp½45:58lnða=50Þ2 
td ¼ 0
if d Þ 0:40 Gy
td ¼ d  0:40 if d . 0:40 Gy:

The model for artificial menopause was constructed in thesame way. Since birth cohort and parity indicated significant
interaction with attained age in the background function,these interaction terms were included with main effects.
The parameters for dose response were shown in Table 5.
The LT model with effect modification by attained age andage at exposure was the model with the best fit (EAR at 1
Gy at age of 50 years for females who were exposed at ageof 20 years ¼ 14.5/1,000 person-years, 95% CI: 10.2, 20.1).
The threshold was estimated to be 0.22 Gy (95% CI: 0.14,0.34). EAR for artificial menopause also peaked at around50 years of age but was modified by attained age in adifferent fashion from natural menopause [(age – 50)2, P ,0.001]. The EAR tended to be the largest at age at exposureof 10 years (P , 0.001). The dose shape and EAR estimatesfor categorized doses are shown in Fig. 3. The model
selected for artificial menopause was
k0 ðc; b; p; s; m; aÞþ 47:4td exp½0:005598ða  50Þ2
 0:9356ðe  10Þ2 =100:Cumulative incidence curves of natural menopause were
illustrated from the age of 30 to 60 years (Fig. 4). The 25th
percentile of age at which the subjects experienced natural
menopause was 49.0, 48.2 and 47.7 years for doses of 0–0.40 Gy (under the threshold), 1 Gy and 1.5 Gy,
respectively. The median ages were 50.9, 50.4 and 50.1
years, respectively. The difference in age between doses of
0–0.40 Gy and 1.5 Gy decreased (1.3 years at the 25th
percentile and 0.8 year at the median). Combined
cumulative incidence of both natural and artificial menopause showed a larger difference than natural menopause;
median ages of menopause were 50.5, 49.3 and 48.4 years

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SAKATA ET AL.

TABLE 5
Parameter Estimates of the Dose–Response Models for Excess Absolute Rate (EAR) for Natural and Artificial Menopause
Natural menopauseModela

b: linearg: quadratict: threshold
Effect modification
Attained age (ln(age/50)2)
Attained age ((age – 50)2)
Age at exposure((atb – 10)2/100)
Deviance
Parameters
AIC

Artificial menopause

Lb

LQ

Q

LT

L

LQ

Q

LT

17.49
–
–
–44.73
–
–

8.19
7.64
–
–
–44.36
–
–

–
12.99
–
–
–43.85
–
–

32.27
–
0.40
–
–45.58
–
–

28.43
–
–
–
–
–0.0049
–0.85

12.1
17.74
–
–
–
–0.0055
–0.90

28.74
–
–
–
–
–0.0060
–0.93

47.36
–
0.22
–
–
–0.0056–0.9441147.06
2641199.06

41145.05
2741199.05

41146.28
2641198.28

41141.70
2741195.70

16272.85
2116314.85

16258.40
2216302.40

16263.00
2116305.00

16257.37
2216301.37

Note. Bolded columns are the selected model.
The EAR model was defined as k0(c,b,p,s,m,a) þ q(d)e(a,e) with city (c), birth year (b), parity (p), smoking status (s), age at menarche (m),attained age (a), radiation dose (d) and age at exposure (e). q(d) was bd for the linear model, bd þ cd2 for linear-quadratic model, cd2 for thequadratic model, b(d – s) when d . s and 0 when d  s for threshold model included s as a threshold.
b
L: linear, LQ: linear-quadratic, Q: quadratic, LT: linear threshold.
a

The primary objective of this study is to investigate theassociation of radiation exposure and age at menopause infemale A-bomb survivors, focusing on the possible latehealth effects of early menopause occurring at least 5 years
after the exposure. A significant association between
radiation and early menopause occurring 5 years or more
after the A-bomb exposure, which excluded early menopause possibly caused by physical injury and psychologicaltrauma immediately after the A-bomb exposure, suggested
that radiation effects on ovarian function may cause theearly onset of menopause. Although dose-dependent effectsof radiotherapy on premature menopause have been
described in several previous studies, most of them werecarried out on cancer survivors who underwent radiotherapy
with extremely high radiation doses such as over 10 Gy (1–5). In contrast, radiation doses of A-bomb survivors are
relatively low compared to those experienced in such
radiotherapy (mean dose among females receiving over0.005 Gy is 0.2 Gy). This study thus provides new evidence
for radiation producing an earlier onset of menopause atlower dose levels.

FIG. 2. Variations of excess absolute rate (EAR) of natural
menopause by weighted ovarian dose. The graph shows excess rates atage 50; there is no effect modification by age at exposure. The thicksolid line is the selected model. The points with error bars are nonparametric estimates.

FIG. 3. Variations of excess absolute rate (EAR) of artificial
menopause by weighted ovarian dose. The graph of EAR shows
excess rates at age 50 for females who were exposed at age 20. The
thick solid line is the selected model. The points with error bars are
non-parametric estimates.

for females exposed to radiation doses of 0–0.22 Gy (under
the threshold), 1 Gy and 1.5 Gy, respectively.
DISCUSSION

AGE AT MENOPAUSE AMONG ATOMIC BOMB SURVIVORS

FIG. 4. Cumulative incidence curves of menopause based on the
final models. Curves shown are those assumed for females who were
exposed in Hiroshima, were born in 1925, were parous, never smokedand experienced menarche at age 15 or 16 years. Ages at the 25th,
50th and 75th percentiles by weighted ovarian dose exposure areshown.

Earlier onset of natural menopause was dose-dependent infemale A-bomb survivors in this study. The magnitude wasestimated to be an 0.8-year advancement at the median ageof natural menopause among those who were exposed to 1.5
Gy. We also found that 20% of females exposed to 1.5 Gy
or more experienced natural menopause before age 45. It isdifficult to directly compare Table 4 and the cumulative
curve in Fig. 4 calculated on the basis of certain females(exposed in Hiroshima, born in 1925, parous, never smoker
and age at menarche of 15 or 16 years). However, the twoare comparable, with the number of females experiencing
menopause before age 45 among females exposed to around
1.5 Gy roughly twice that of females exposed to 0 Gy. Germcell damage from radiation is thought to be one of the793

possible causes of ovarian failure and premature menopause(16, 17). The human ovary contains a fixed pool ofprimordial follicles, reaching a maximum quantity at 5
months of gestational age that then declines with increasingage. The mechanism of menopause is yet to be fully
explained, but it is thought that when the number of oocytes
declines to approximately 1,000, menopause is experienced(18). Thus the damage of oocytes by radiation and theconsequent decrease in the number of pooled oocytes arethought to hasten menopause.
The dose response of radiation effects on natural
menopause was linear with a threshold of 0.40 Gy. Wallace
et al. reported a model for predicting the age at which
ovarian failure is likely to develop after radiation therapy(19). The LD50 of the human oocyte estimated to be lessthan 2 Gy (17), and therefore radiation exposure of 0.40 Gy
is estimated to reduce the number of oocytes by 13%.
Although the reduction of oocytes may be sufficient to
induce premature menopause according to Wallace’s
hypothesis, no excess of premature menopause wasobserved at the level of 0.4 Gy in our study. Their studies
were based on high-dose radiation such as in radiotherapy,
and they extrapolated the effects to low doses, so a
threshold may not have been detectable. On the other hand,such small effects at the level of 0.4 Gy or lower may nothave been detected in our study because information on age
at menopause was obtained in 1-year units and menopause
occurs frequently in a short age range. In addition, uncertain
memories and unclear definitions about menopause, discussed later, may reduce the detection power because of
nondifferential misclassification. No information is available on the threshold value for killing of human oocytes toour knowledge, but the possibility of biological repair of thedamaged follicles has been suggested (20).
The number of females experiencing artificial menopause
increased with radiation dose, and the age at artificial
menopause decreased with dose. Although causes ofartificial menopause were not asked for in any of the mailsurveys, 43.6% of females experiencing artificial menopause reported a history of myoma in the surveys, 5.2%
reported uterine cancer, 1.2% reported ovarian cancer, and30.7% reported unknown disease of the uterus or ovary. In
previous studies on A-bomb survivors, significant associations with radiation were observed for myoma, ovariancancer and uterine cancer among females who were exposedat young ages (11, 21). The increasing prevalence ofartificial menopause with increasing radiation dose isthought to be caused by the increasing possibility ofhysterectomy or oophrectomy due to such diseases among
exposed females.
Ever-smokers compared to never-smokers and nulliparous females compared to parous females tended toexperience earlier menopause in this study. Those results
were consistent with those observed in some previous
analyses of the relationship between lifestyle and age atmenopause (22–27). The prevalence of ever-smokers and794

SAKATA ET AL.

nulliparous females tended to increase in those with highradiation doses to the ovary (data not shown). Based on thefindings, those factors were incorporated into the background function to adjust for them.
Age at menopause of the subjects was determined by selfreports in the mail surveys in this study. Many studies
adopted the definition by the World Health Organization(WHO) for natural menopause (28). The WHO definition isthat ‘‘[n]o menses for 12 consecutive months with no
obvious cause (such as pregnancy, lactation) will retrospectively define a women’s last menstrual period’’ (29).
Respondents replied to questions about age at menopause
in accordance with their own individual definition ofmenopause, which might not have met the WHO definition.
Some females might have replied to the question byconsidering of the age of permanent cessation of menses,
but some might have replied regarding age at amenorrhea
without 12 months passing since cessation. There mightalso have been recall errors, especially for replies long after
menopause occurred. However, it is difficult to clarify how
respondents defined their menopause experience and how
such recall errors were related to radiation dose, if at all.
With respect to reproducibility of age at menopause
among the subjects who replied to two mail surveys or
more, 70.4% of females reported ages within 62 years
between the two surveys. There was no tendency for older
subjects to report later ages at menopause and vice versa,
and the distribution of the differences in age displayed
bilateral symmetry (data not shown). That fact suggested ahigh reproducibility of self-reported age at menopause via
mail surveys despite long intervals of about 10 years
between the surveys.
Some studies have observed secular trends of age atmenopause shifting toward older ages (30, 31). However,
the eldest birth cohort reported the oldest age at menopause
in this study. In the eldest birth cohort in this study, those
who experienced menopause before 1950 were excluded
from the analysis; i.e., those who experienced menopause atyoung ages were excluded. In addition, in the recent birthcohorts, many females were not followed up to old ages andmay not have reached menopause, and consequently thereported ages at menopause were shifted toward younger
ages. Therefore, birth cohort effects in this study did notcontradict the previous reports and a similar study should be
performed to evaluate birth cohort effects after the entire
LSS cohort reaches menopause.
In conclusion, age at menopause decreases with increasing radiation dose among female A-bomb survivors formenopause occurring 5 years or more after the exposure.
The radiation effects were significant on natural menopause,
which suggested effects of radiation on ovarian function.
Effects were also observed in artificial menopause, whichmight be related to an increasing incidence of myoma anduterine and ovarian cancers, which are known to have asignificant relationship to radiation exposure.

ACKNOWLEDGMENTS
The Radiation Effects Research Foundation (RERF), Hiroshima andNagasaki, Japan is a private, non-profit foundation funded by the Japanese
Ministry of Health, Labour and Welfare (MHLW) and the U.S.
Department of Energy (DOE), the latter in part through the National
Academy of Sciences. We thank the RERF Master File Section for its hard
work in assembling the mail survey information and maintaining therelevant data.
Received: May 16, 2011; accepted September 16, 2011; published online:
October 11, 2011

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