Factors associated with age of onset and type of menopause in a cohort of UK women

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GENERAL GYNECOLOGY

Factors associated with age of onset and type of menopause in a cohort of UK women Alida J. Pokoradi, MSc; Lisa Iversen, PhD; Philip C. Hannaford, MD OBJECTIVE: We sought to describe the pattern of age at menopause

and factors associated with type of menopause. STUDY DESIGN: This was a prospective cohort study of 5113 post-

ilization, and history of endometriosis (all increased odds ratios) and ever-use of hormone replacement therapy (decreased). Surgical menopause was associated with manual social class, sterilization, and having a history of endometriosis, menorrhagia, or painful menstruation (all increased), and ever-use of hormone replacement therapy (decreased).

menopausal health survey respondents in the Royal College of General Practitioners’ Oral Contraception Study. Logistic regression was used to evaluate associations between sociodemographics, lifestyle, and medical history and menopause type.

CONCLUSION: Age at natural menopause was younger in this cohort

RESULTS: Median age at natural menopause (n ⫽ 3650) was 49.0

than in other studies. More associations were found for surgical menopause than early natural menopause.

years (interquartile range, 45.0 –51.0), and at surgical menopause (n ⫽ 1463) was 42.4 years (38.0 – 46.4). Early natural menopause was associated with smoking, ever-use of oral contraception, ster-

Key words: age, menopause, natural menopause, onset, risk factors, surgical menopause

Cite this article as: Pokoradi AJ, Iversen L, Hannaford PC. Factors associated with age of onset and type of menopause in a cohort of UK women. Am J Obstet Gynecol 2011;205:34.e1-13.

M

enopause is an important point in a woman’s life because it signals the end of her reproductive life. The menopause transition is often accompanied by a number of symptoms, such as

From the Centre of Academic Primary Care, University of Aberdeen, Aberdeen, Scotland, United Kingdom. Received Sept. 23, 2010; revised Jan. 6, 2011; accepted Feb. 17, 2011. Reprints not available from the authors. The health survey was funded by an unconditional grant from Wyeth-Ayerst International Inc, Madison, NJ. The Royal College of General Practitioners’ Oral Contraception Study has received funding from the Royal College of General Practitioners, Medical Research Council, Imperial Cancer Research Fund (now Cancer Research UK), British Heart Foundation, Cruden Foundation, Chief Scientist Office Scotland, Schering AG, Schering Health Care Ltd, Ortho Cilag, and Searle. The Centre of Academic Primary Care has received payments from Schering Plough and Wyeth Pharmaceuticals for lectures and advisory board work provided by Dr Hannaford in relation to hormone replacement therapy and oral contraception. 0002-9378/$36.00 © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.02.059

34.e1

vasomotor symptoms and vaginal atrophy.1,2 A woman’s age at menopause may affect the type and severity of her menopausal symptoms. A prospective cohort study of 6917 Swedish women found that those aged ⬎53 years at natural menopause had reduced frequency and intensity of vaginal dryness and atrophy, but increased frequency of hot flashes than women experiencing menopause at a younger age.3 Age at menopause may also influence subsequent health. A prospective study of 5287 Californian women showed that young age at natural menopause (⬍40 years) was associated with an increased risk of subsequent all-cause mortality compared to natural menopause occurring at 50-54 years.4 Other studies have shown that earlier age at both natural and surgical menopause is a risk factor for future osteoporosis5 and cardiovascular disease.6 Age at menopause is likely to be affected by numerous genetic, environmental, and sociodemographic factors that differ between populations. Cigarette smoking has been consistently shown to affect menopause onset, with smokers frequently reaching menopause as much as 1.5 years sooner than nonsmokers,7 and smokers at greater risk of

American Journal of Obstetrics & Gynecology JULY 2011

surgical menopause than nonsmokers.8 Evidence regarding the effects of other sociodemographic and lifestyle factors (eg, social class, alcohol consumption, body mass index [BMI], parity, prior oral contraceptive [OC] use) on age and type of menopause are conflicting. Age at menopause has been investigated in US,9-14 Dutch,15,16 and Australian17,18 women, but only to a small extent in United Kingdom women.19 Due to its possible association with future ill health, it is important to know the mean age at, and factors associated with, menopause in United Kingdom women. We report here our findings from the ongoing Royal College of General Practitioners’ (GPs) Oral Contraception Study (RCGP OCS).

M ATERIALS AND M ETHODS The RCGP OCS Beginning in May 1968, 1400 GPs across the United Kingdom recruited approximately 23,000 women who were using OCs and a comparable number of women who had never done so.20 Participants were mostly white (98%) and all were either married or living as married. Both pill users and never-users were of a similar age (mean 29 years, SD 6.6 years) at recruitment. Information collected at

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cedures (1969)22 for any surgery. Women were lost from GP follow-up if they left the recruiting practice, they received OC from a different source (eg, a family planning clinic), they died, or their GP withdrew from the study.20 From November 1994 through July 1995, most of the 12,303 women who were still under GP observation were sent a health survey questionnaire by their GP on our behalf.23 The health survey collected information about: parity, lifetime cigarette smoking, weekly alcohol consumption, current height and weight, weight at age 30 years, weekly hours of physical activity, whether the respondent had ever had a hysterectomy or been through menopause, and the month and year of her final menstrual period (FMP).

FIGURE 1

Flowchart of patients through cohort

FMP, final menstrual period; GP, general practitioner; RCGP OCS, Royal College of General Practitioners’ Oral Contraception Study. Pokoradi. Risk factors for age and type of menopause. Am J Obstet Gynecol 2011.

baseline included social class (as determined by the woman’s husband’s occupation), significant medical history, previous OC use, and parity. Following recruitment, information was received from the participating GPs every 6 months about: hormonal preparations

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prescribed, pregnancies, surgery, new episodes of illness, and, if applicable, date and cause of death. Information from the GPs was coded using the International Classification of Diseases (8th revision)21 for morbidity and deaths, and the Code of Surgical Operations and Pro-

The study sample The study sample consisted of all postmenopausal women who returned the health survey questionnaire and who reported valid information about the timing of their FMP (Figure 1). To check that the health survey was sent to the correct woman, health survey data were compared with RCGP OCS data and any women with discrepant information excluded (n ⫽ 48). Type of menopause (natural or surgical) and age at menopause was determined using the process detailed in Figure 2. The RCGP OCS records were checked for a recording of hysterectomy and/or oophorectomy (Surgical Operations and Procedures R codes R671-672, R681, R690-694, R696) by October 1994. When a woman had no operations recorded, her responses to the health survey were examined. If a woman had reported having gone through menopause and had provided a date for the event, the midpoint of the corresponding year (June) was taken when calculating her age at menopause. We took the year midpoint because many women reporting their FMP failed to give the month as well as the year of the event. These women were allocated to the natural menopause group. We excluded women without a recording of an operation who had not finished their periods (n ⫽ 3574), those who did not provide the year of their FMP (n ⫽ 1210), those whose calculated

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FIGURE 2

Algorithm for determining type of and age at menopause

FMP, final menstrual period; RCGP OCS, Royal College of General Practitioners’ Oral Contraception Study. Pokoradi. Risk factors for age and type of menopause. Am J Obstet Gynecol 2011.

age at menopause seemed particularly young (⬍25 years) or old (⬎60 years; n ⫽ 24) as we suspect these data might be incorrect, women who had a hysterectomy prior to recruitment to the RCGP OCS (n ⫽ 25), and women who had a pregnancy after her reported date of menopause (n ⫽ 13). If a woman had a record of hysterectomy and/or oophorectomy, her health survey responses were examined to see whether she also reported a date of menopause. If the respondent did not report the date of FMP on the health survey, the date of her operation was used to calculate the age at menopause and her menopause was considered to be surgical (n ⫽ 434). Women aged ⱖ55 years at time of operation (n ⫽ 58) were excluded from this group because they 34.e3

were likely to have been through natural menopause before this age although the age at menopause was unknown. If a date of FMP was reported in the health survey, both age at operation and age at reported date of menopause were calculated. If the age at operation was less than or equal to the reported age of menopause, the woman was allocated to the surgical menopause group (n ⫽ 1029) and the age at operation taken as the age at menopause. Women were excluded (n ⫽ 8) from this group if their age at operation was particularly young (⬍25 years) or old (⬎60 years). If a woman’s age at operation was older than her age at menopause reported in the health survey, her menopause was considered to be natural and the age at menopause based on the survey response used (n ⫽ 541).

American Journal of Obstetrics & Gynecology JULY 2011

For each postmenopausal woman, information recorded on the RCGP OCS database between recruitment to the main study and age at menopause were extracted for: social class, OC and hormone replacement therapy (HRT) use, any record of tubal sterilization, recorded menstrual difficulties (ie, endometriosis, menorrhagia, and painful menstruation), any cancer, and autoimmune disease (ie, diabetes, rheumatoid arthritis, inflammatory bowel disease, and thyroid disease). This information was supplemented by health and lifestyle data reported by respondents in the health survey: pack-years smoked, weekly alcohol consumption, weekly physical activity, BMI at age 30 years, and parity.

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FIGURE 3

Histogram for age at any menopause

IQR, interquartile range. Pokoradi. Risk factors for age and type of menopause. Am J Obstet Gynecol 2011.

Statistical analysis Data were analyzed using software (SPSS for Windows, version 17.0.1; SPSS, Chicago, IL). Age at menopause was examined among all postmenopausal respon-

dents in the health survey, those with a natural menopause and those with a surgical menopause. We then completed separate analyses to examine the relationship between age at menopause and

FIGURE 4

Histogram for age at natural menopause

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lifestyle, personal characteristics, reproductive, gynecological, and other medical history among women having a natural menopause, and similar relationships between natural or surgical menopause. When investigating naturally postmenopausal women, 2 groups were created, stratified by the median age at menopause in that group. Thus, women who were younger than (referred to as “early natural menopause”) were compared with those older than the median age (“later natural menopause”). The characteristics of women in these 2 natural menopause groups were compared using ␹2 tests for categorical variables. The ␹2 tests were also used to compare the characteristics of women with natural menopause to women with surgical menopause. Statistical significance was set at P ⱕ .01 in all analyses because of the large number of comparisons being made. Unadjusted odds ratios (ORs) and their 99% confidence intervals (CIs) were calculated for each variable using binary logistic regression. The 2 outcomes were early natural menopause and surgical menopause. Confounders were decided upon a priori, based on frequent associations in the literature between age at menopause and OC use, social class, and smoking. Age in 1995 was also included in the model examining factors associated with surgical menopause, to account for the influence of aging. Adjusted ORs (and their 99% CIs) were calculated once the confounders were entered into the model. For consistency a missing value category was included for each variable.

Details of ethics approval The RCGP OCS began before multicenter research ethics committees were introduced in the United Kingdom. The procedure we used, however, maintained participant confidentiality. All correspondence between participating GPs and the RCGP OCS used a unique study number for each woman, the key to which only the GPs held.

R ESULTS IQR, interquartile range. Pokoradi. Risk factors for age and type of menopause. Am J Obstet Gynecol 2011.

Median age at menopause Median age at menopause among all 5113 postmenopausal respondents to JULY 2011 American Journal of Obstetrics & Gynecology

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the health survey was 47.2 years (interquartile range [IQR], 43.0 –50.2) (Figure 3). There were 3650 women with a natural menopause, occurring at a median age of 49.0 years (IQR, 45.0 –51.0) (Figure 4). The median age at menopause among the 1463 women with a surgical menopause was 42.4 years (IQR, 39.0 – 46.4) (Figure 5). Median age at natural menopause, stratified by birth decade, is shown in Table 1. Although birth years of respondents with natural menopause ranged from 1919 through 1950, there was an insufficient number of women born in 1919 and 1950 for inclusion in the analysis. Table 1 shows that the median age at natural menopause was similar among each of the birth decades examined. Trends in surgical menopause, however, have changed throughout these 3 decades. While 8.3% of women born from 1920 through 1929 experienced a surgical menopause, 18.0% and 52.9% of women born from 1930 through 1939 and 1940 through 1949 experienced a surgical menopause, respectively.

Characteristics associated with an early rather than late menopause Women with an early natural menopause were significantly more likely to be of manual social class than women with a later natural menopause, when assessed univariately but not after adjustment (Table 2). Fifteen or more pack-years of smoking was significantly more common on both univariate and multivariate analysis among women in the early natural menopause group than those in the later group. Overall, smokers in our study had a mean age at menopause of 45.6 years (SD 6.04 years) while nonsmokers’ mean age at menopause was 46.9 years (SD 5.7 years). Age at natural menopause was not associated with weekly alcohol consumption, physical activity, BMI at age 30 years, or parity. Women with an early natural menopause were significantly more likely to be: ever-users of OC; sterilized; and have at least 1 episode of endometriosis, than women with a later natural menopause, but they were less likely to have used HRT than the later natural menopause group. Ever-users of OC in our study had 34.e5

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FIGURE 5

Histogram for age at surgical menopause

IQR, interquartile range. Pokoradi. Risk factors for age and type of menopause. Am J Obstet Gynecol 2011.

a mean age at menopause of 45.7 years (SD 6.00 years) while never-users’ mean age at menopause was 47.2 years (SD 5.50 years). There were no other significant differences between the 2 groups.

Characteristics associated with a surgical rather than natural menopause Most women who had hysterectomy recorded either also had a partial oophorectomy or there was no information supplied about whether 1 or both ovaries had been removed (1149/1463, 78.5%). Thus, only 314 women (21.5%) had definite bilateral oophorectomy recorded. Women with surgical menopause were significantly more likely to be of manual social class than women with natural

menopause, before and after adjustment (Table 3). Women with surgical menopause tended to have higher BMIs at 30 years of age than women with natural menopause, although the ORs were not statistically significant after adjustment. There were no differences between type of menopause in terms of pack-years of smoking, weekly alcohol consumption, physical activity, or parity. Compared with naturally postmenopausal women, women with surgical menopause were more likely to be sterilized and to have at least one episode of endometriosis, menorrhagia, or painful menstruation, but less likely to use HRT. Most of these associations remained after multivariate adjustment. There were no

TABLE 1

Median age at natural menopause by birth year decade Median age at natural menopause (interquartile range)

Birth year decade

Age at health survey in 1995, y

1920 through 1929

66–75

538

49.0 (46.0–52.0)

1930 through 1939

56–65

2321

49.0 (46.0–52.0)

1940 through 1949

46–55

786

47.0 (44.0–49.0)

n

.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................

Pokoradi. Risk factors for age and type of menopause. Am J Obstet Gynecol 2011.

American Journal of Obstetrics & Gynecology JULY 2011

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TABLE 2

Factors associated with age at natural menopause Age at menopause

Characteristic

All

<49 y

>49 y

(n ⴝ 1691)

(n ⴝ 1959)

Unadjusted OR

n

n

(%)

(99% CI)

(%)

Adjusted ORa P value

(99% CI)

P value

SOCIAL CLASS AT RECRUITMENT TO RCGP OCS Nonmanual

1375

582

(34.4)

793

(40.5)

1.00b

Manual

2268

1104

(65.3)

1164

(59.4)

1.29 (1.08–1.54)

Missing

7

5

(0.3)

2

(0.1)

1949

810

(47.9)

1139

⬍15

528

231

(13.7)

15–30

552

313

⬎30

466

Missing

155

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

⬍ .001

1.17 (0.97–1.40)

.029

................................................................................................................................................................................................................................................................................................................................................................................

—

—

(58.1)

1.00b

1.00b

297

(15.2)

1.09 (0.85–1.41)

.366

1.07 (0.83–1.39)

.477

(18.5)

239

(12.2)

1.84 (1.43–2.37)

⬍ .001

1.75 (1.36–2.25)

⬍ .001

263

(15.6)

203

(10.4)

1.82 (1.39–2.38)

⬍ .001

1.71 (1.30–2.24)

⬍ .001

74

(4.4)

81

(4.1)

................................................................................................................................................................................................................................................................................................................................................................................

PACK-YEARS SMOKED 0

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

—

—

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

NO. OF U OF ALCOHOL DRUNK/WK 0

862

413

(24.4)

449

(22.9)

1.00b

⬍1

535

258

(15.3)

277

(14.1)

1.01 (0.76–1.35)

.910

1.11 (0.83–1.48)

.370

1–4

969

442

(26.1)

527

(26.9)

0.91 (0.72–1.16)

.325

0.96 (0.75–1.23)

.671

⬎4

918

406

(24.0)

512

(26.1)

0.86 (0.68–1.10)

.119

0.82 (0.64–1.06)

.044

Missing

366

172

(10.2)

194

(9.9)

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

—

—

................................................................................................................................................................................................................................................................................................................................................................................

PHYSICAL ACTIVITY, H/WK Light, ⬍16

1139

549

(32.5)

590

(30.1)

1.17 (0.94–1.45)

.065

Moderate, 16–29

1286

596

(35.2)

690

(35.2)

1.08 (0.88–1.33)

.327

Heavy, ⬎29

1183

525

(31.0)

658

(33.6)

1.00

1.00

42

21

(1.2)

21

(1.1)

—

—

1.22 (0.71–2.10)

1.13 (0.91–1.41)

.146

1.08 (0.87–1.33)

.361

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ b b ................................................................................................................................................................................................................................................................................................................................................................................

Missing

................................................................................................................................................................................................................................................................................................................................................................................ 2

BODY MASS INDEX (KG/M ) AT 30 Y OF AGE

⬍18.50

94

48

(2.8)

46

(2.3)

.338

1.09 (0.63–1.89)

.687

18.50–24.99

2786

1283

(75.9)

1503

(76.7)

1.00

25.00–29.99

572

265

(15.7)

307

(15.7)

1.01 (0.80–1.28)

.904

ⱖ30

147

68

(4.0)

79

(4.0)

1.01 (0.65–1.56)

.961

51

27

(1.6)

24

(1.2)

—

—

0

159

73

(4.3)

86

(4.4)

1.00b

1.00b

1

401

179

(10.6)

222

(11.3)

0.95 (0.59–1.54)

.785

0.85 (0.52–1.39)

.389

2

1430

654

(38.7)

776

(39.6)

0.99 (0.64–1.53)

.966

0.89 (0.57–1.39)

.504

3⫹

1558

726

(42.9)

832

(42.5)

1.03 (0.67–1.58)

.869

0.87 (0.56–1.35)

.407

102

59

(3.5)

43

(2.2)

................................................................................................................................................................................................................................................................................................................................................................................ b b

1.00

................................................................................................................................................................................................................................................................................................................................................................................

1.02 (0.80–1.30)

.807

0.97 (0.62–1.52)

.880

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Missing

................................................................................................................................................................................................................................................................................................................................................................................

PARITY ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Missing

—

—

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

ORAL CONTRACEPTIVE USE UP TO AGE AT MENOPAUSE Never

1544

632

(37.4)

912

(46.6)

1.00b

Ever

2004

1000

(59.1)

1004

(51.3)

1.44 (1.21–1.71)

102

59

(3.5)

43

(2.2)

................................................................................................................................................................................................................................................................................................................................................................................

⬍ .001

1.37 (1.14–1.63)

⬍ .001

................................................................................................................................................................................................................................................................................................................................................................................

Missing

—

—

................................................................................................................................................................................................................................................................................................................................................................................

Pokoradi. Risk factors for age and type of menopause. Am J Obstet Gynecol 2011.

(continued )

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TABLE 2

Factors associated with age at natural menopause

(continued)

Age at menopause

Characteristic

All

<49 y

>49 y

(n ⴝ 1691)

(n ⴝ 1959)

Unadjusted OR

n

n

(99% CI)

(%)

(%)

Adjusted ORa P value

(99% CI)

P value

HORMONE REPLACEMENT THERAPY USE UP TO AGE AT MENOPAUSE Never

3249

1564

(92.5)

1685

(86.0)

1.00b

Ever

299

68

(4.0)

231

(11.8)

0.32 (0.22–0.46)

Missing

102

59

(3.5)

43

(2.2)

No

3308

1499

(88.6)

1809

(92.3)

Yes

342

192

(11.4)

150

(7.7)

3352

1626

(96.2)

1926

(98.3)

98

65

(3.8)

33

(1.7)

No

2533

1157

(68.4)

1376

(70.2)

1.00b

Yes

1117

534

(31.6)

583

(29.8)

1.09 (0.91–1.31)

1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

⬍ .001

0.28 (0.20–0.41)

⬍ .001

................................................................................................................................................................................................................................................................................................................................................................................

—

—

................................................................................................................................................................................................................................................................................................................................................................................

TUBAL STERILIZATION 1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

1.55 (1.15–2.07)

⬍ .001

1.38 (1.02–1.87)

.006

................................................................................................................................................................................................................................................................................................................................................................................

ENDOMETRIOSIS No

1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

Yes

2.33 (1.34–4.07)

⬍ .001

2.49 (1.42–4.37)

⬍ .001

................................................................................................................................................................................................................................................................................................................................................................................

MENORRHAGIA 1.00b

................................................................................................................................................................................................................................................................................................................................................................................

.234

1.09 (0.90–1.31)

.255

................................................................................................................................................................................................................................................................................................................................................................................

PAINFUL MENSTRUATION No

3403

1567

(92.7)

1836

(93.7)

Yes

247

124

(7.3)

123

(6.3)

3575

1657

(98.0)

1918

(97.9)

75

34

(2.0)

41

(2.1)

3555

1647

(97.4)

1908

(97.4)

95

44

(2.6)

51

(2.6)

3565

1646

(97.3)

1919

(98.0)

85

45

(2.7)

40

(2.0)

3627

1680

(99.3)

1947

(99.4)

23

11

(0.7)

12

(0.6)

No

3404

1575

(93.1)

1829

(93.4)

Yes

246

116

(6.9)

130

(6.6)

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

1.18 (0.84–1.66)

.207

1.13 (0.80–1.59)

.369

................................................................................................................................................................................................................................................................................................................................................................................

RECORD OF CANCER No

1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

Yes

0.96 (0.53–1.76)

.861

1.03 (0.56–1.91)

.888

................................................................................................................................................................................................................................................................................................................................................................................

DIABETES No

1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

Yes

1.00 (0.58–1.71)

.998

1.00 (0.58–1.73)

.985

................................................................................................................................................................................................................................................................................................................................................................................

RHEUMATOID ARTHRITIS No

1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

Yes

1.31 (0.74–2.31)

.217

1.23 (0.69–2.19)

.354

................................................................................................................................................................................................................................................................................................................................................................................

INFLAMMATORY BOWEL DISEASE No

1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

Yes

1.06 (0.36–3.12)

.885

1.00 (0.33–2.99)

.996

................................................................................................................................................................................................................................................................................................................................................................................

THYROID DISEASE 1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

1.04 (0.74–1.46)

.788

1.03 (0.73–1.45)

.833

................................................................................................................................................................................................................................................................................................................................................................................

P values calculated using binary logistic regression. CI, confidence interval; OR, odds ratio; RCGP OCS, Royal College of General Practitioners’ Oral Contraception Study. a

Adjusted for social class, pack-years of smoking, and oral contraceptive use up to age at menopause, except where that particular variable was examined; b Referent.

Pokoradi. Risk factors for age and type of menopause. Am J Obstet Gynecol 2011.

differences between type of menopause and history of cancer or autoimmune diseases. Comparison of women with definite bilateral oophorectomy with women who had hysterectomy but unknown oo34.e7

phorectomy status showed no difference in personal characteristics (eg, social class, smoking, alcohol intake, BMI, parity) but those with definite bilateral oophorectomy were less likely to have used

American Journal of Obstetrics & Gynecology JULY 2011

OC (OR, 0.66; 99% CI, 0.47– 0.94), and more likely to have used HRT prior to operation (OR, 5.40; 99% CI, 3.20 – 9.11), have a history of endometriosis (OR, 1.70; 99% CI, 1.06 –2.73), and have

www.AJOG.org a record of cancer (OR, 2.62; 99% CI, 1.12– 6.16). There were no other differences in medical history.

C OMMENT Summary of findings Among respondents to the RCGP OCS health survey, age at menopause was influenced by whether the event occurred naturally or was induced by hysterectomy and/or oophorectomy. Median age of natural menopause was 49.0 years in this cohort, and was 42.4 years after surgical menopause. Compared to women with later natural menopause, those who had early natural menopause were more likely to be: smokers; ever-users of OC; sterilized; and have a history of endometriosis, but less likely to have ever used HRT. Women with a surgical, rather than natural, menopause were more likely to be: of manual social class; sterilized; and have a history of endometriosis, menorrhagia, or painful menstruation, but less likely to have ever used HRT. Strengths and limitations of the study The original purpose of the RCGP OCS was to examine the health risks of OC. There is no reason to suspect that women were identified by the participating GPs on the basis of their future risk of early or late age at menopause or surgical menopause. Selection bias at recruitment is therefore unlikely to have affected our results. The cohort, however, is healthier than the general population; this will affect generalizability but will not affect internal comparisons within the cohort. Prospective collection of comprehensive medical information during the RCGP OCS allowed examination of numerous potential risk factors. Most of the information was based on that supplied by the participating GPs. This information was often supplemented by additional information from any hospital referrals or tests. Furthermore, many clinical events become confirmed or refuted as time takes place–the longitudinal nature of the study meant that when an initial diagnosis changed the database could be updated with the correct information. All reported events were coded

General Gynecology by 2 coders who went back to the reporting GP for more information if the event was not clear, or if other information was missing (eg, before an operation was coded we reviewed the information held for that woman to see if there was a logical explanation for the operation, and if not we wrote to the GP asking for a reason for the operation). Over the past 40 years we had conducted specific audits of some events reported by the GPs (eg, strokes and breast cancer), and generally found a high level of confirmation for the diagnoses. There has not, however, been a routine verification of data from the GPs. Health survey information was supplied by women who remained in the study until the mid-1990s. If women who were lost to follow-up prior to receiving the health survey differed systematically in terms of age at menopause than women still under GP observation at that time, bias would have occurred. Most participants, however, were lost to follow-up because they moved from the recruiting GP or their GP left the study, factors that are unlikely to be related to age at menopause. Bias could have also occurred if excluded women who provided incomplete or no date of FMP were systematically different to included women who provided complete information about this variable. Recall bias might have affected health survey variables if women with early or surgical menopause recalled certain events (eg, age at menopause, lifestyle factors) differently from women with later or natural menopause. Associations between ethnicity and age at menopause could not be explored because most of the participants in the RCGP OCS were white Europeans (98%). RCGP OCS participants have been shown to have a lower standardized mortality rate than the national average, meaning that recruited women were healthier than average United Kingdom women.24 This potentially limits generalizability of our results to the wider population. Only the midpoint of year of FMP was used to calculate the age at natural menopause of respondents to the health survey because many women failed to give the month of FMP. However, distribution of month of FMP was likely to be

Research

spread across the entire year, and so use of the midpoint should minimize any effects of misclassification of age at menopause. Confounders were chosen a priori when calculating adjusted ORs. However, it is possible that residual confounding from factors not measured in the study (eg, diet, family history) might have affected our results. In the main analysis, all women with hysterectomy and/or oophorectomy were considered together. This is partly because most of the women in this group had been reported to have had a hysterectomy with only partial oophorectomy or without any information supplied about whether one or both ovaries had also been removed. Furthermore, even if the ovaries were conserved we did not know if the operation had led to early menopause due to compromised ovarian blood supply.25 Thus, the proportion of women with surgical menopause in this study may have been overestimated due to the assumption that women with hysterectomy also had their ovaries removed at the operation.

Early natural menopause Nearly three-quarters of the postmenopausal health survey respondents experienced natural menopause. Median age at natural menopause was low compared with other reports. The Medical Research Council’s National Survey of Health and Development has prospectively followed 2547 British women since their birth during 1 week in March 1946.19 Median age at natural menopause in that cohort was 50 years and 11 months (IQR not specified) when participants were asked about the timing of their menopause at age 57 (n ⫽ 1583). A Dutch breast cancer screening cohort of 4868 women born from 1911 through 1925 had a mean age at natural menopause of 50.2 years (SD 4.15).15 The North American Study of Women’s Health Across the Nation found a median age of natural menopause among white participants of 51.4 years (IQR not specified),10 and the Massachusetts Women’s Health Study of 7828 women aged 45-55 years prospectively followed up from 1982 through 1985 found a median of 51.4 years (IQR not specified; SE 0.19).26

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TABLE 3

Factors associated with surgical menopause Type of menopause

Characteristic

All

Surgical

Natural

(n ⴝ 1463)

(n ⴝ 3650)

Unadjusted OR

n

n

(%)

(99% CI)

(%)

Adjusted ORa P value

(99% CI)

P value

SOCIAL CLASS AT RECRUITMENT TO RCGP OCS Nonmanual

1776

401

(27.4)

1375

(37.7)

1.00b

Manual

3326

1058

(72.3)

2268

(62.1)

1.60 (1.34–1.91)

Missing

11

4

(0.3)

7

(0.2)

2690

741

(50.6)

1949

⬍15

761

233

(15.9)

15–30

783

231

⬎30

647

Missing

232

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

⬍ .001

1.25 (1.03–1.52)

.003

................................................................................................................................................................................................................................................................................................................................................................................

—

—

(53.4)

1.00b

1.00b

528

(14.5)

1.16 (0.92–1.46)

.097

1.02 (0.79–1.33)

.814

(15.8)

552

(15.1)

1.10 (0.87–1.39)

.284

0.81 (0.63–1.05)

.040

181

(12.4)

466

(12.8)

1.02 (0.79–1.31)

.827

0.93 (0.70–1.24)

.534

77

(5.3)

155

(4.2)

1185

323

(22.1)

862

⬍1

752

217

(14.8)

1–4

1353

384

⬎4

1291 532

................................................................................................................................................................................................................................................................................................................................................................................

PACK-YEARS SMOKED 0

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

—

—

(23.6)

1.00b

1.00b

535

(14.7)

1.08 (0.83–1.41)

.444

0.98 (0.73–1.32)

.842

(26.2)

969

(26.5)

1.06 (0.84–1.33)

.529

0.96 (0.74–1.24)

.674

373

(25.5)

918

(25.2)

1.08 (0.86–1.37)

.366

0.91 (0.70–1.18)

.338

166

(11.3)

366

(10.0)

—

................................................................................................................................................................................................................................................................................................................................................................................

NO. OF U OF ALCOHOL DRUNK/WK 0

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Missing

—

................................................................................................................................................................................................................................................................................................................................................................................

PHYSICAL ACTIVITY, H/WK Light, ⬍16

1607

468

(32.0)

1139

(31.2)

1.05 (0.86–1.29)

.513

0.95 (0.76–1.19)

.541

Moderate, 16–29

1800

514

(35.1)

1286

(35.2)

1.02 (0.84–1.24)

.760

0.93 (0.75–1.15)

.376

Heavy, ⬎29

1645

462

(31.6)

1183

(32.4)

1.00

1.00

61

19

(1.3)

42

(1.2)

—

—

1.30 (0.81–2.08)

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ b b ................................................................................................................................................................................................................................................................................................................................................................................

Missing

................................................................................................................................................................................................................................................................................................................................................................................ 2

BODY MASS INDEX (KG/M ) AT 30 Y OF AGE

⬍18.50

94

48

(2.8)

46

(2.3)

.156

1.23 (0.73–2.09)

.311

18.50–24.99

3837

1051

(71.8)

2786

(76.3)

1.00

25.00–29.99

848

276

(18.9)

572

(15.7)

1.28 (1.04–1.58)

.003

1.26 (0.99–1.60)

.012

ⱖ30

219

72

(4.9)

147

(4.0)

1.30 (0.89–1.90)

.078

1.08 (0.71–1.66)

.631

69

18

(1.2)

51

(1.4)

—

—

0

225

66

(4.5)

159

(4.4)

1.00b

1.00b

1

558

157

(10.7)

401

(11.0)

0.94 (0.60–1.48)

.737

0.77 (0.47–1.28)

.189

2

2051

621

(42.4)

1430

(39.2)

1.05 (0.70–1.56)

.770

0.78 (0.49–1.22)

.150

ⱖ3

2177

619

(42.3)

1558

(42.7)

0.96 (0.64–1.42)

.776

0.84 (0.53–1.32)

.308

102

0

(0.0)

102

(2.8)

................................................................................................................................................................................................................................................................................................................................................................................ b b

1.00

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Missing

................................................................................................................................................................................................................................................................................................................................................................................

PARITY ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Missing

—

—

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

ORAL CONTRACEPTIVE USE UP TO AGE AT MENOPAUSE Never

2027

483

(33.0)

1544

(42.3)

1.00b

Ever

2984

980

(67.0)

2004

(54.9)

1.56 (1.32–1.85)

102

0

(0.0)

102

(2.8)

................................................................................................................................................................................................................................................................................................................................................................................

⬍ .001

1.15 (0.96–1.39)

.053

................................................................................................................................................................................................................................................................................................................................................................................

Missing

—

—

................................................................................................................................................................................................................................................................................................................................................................................

Pokoradi. Risk factors for age and type of menopause. Am J Obstet Gynecol 2011.

34.e9

American Journal of Obstetrics & Gynecology JULY 2011

(continued )

General Gynecology

www.AJOG.org

Research

TABLE 3

Factors associated with surgical menopause

(continued)

Type of menopause Surgical

Natural

(n ⴝ 1463)

(n ⴝ 3650)

Adjusted ORa

Unadjusted OR

Characteristic All n (%) n (%) HORMONE REPLACEMENT THERAPY USE UP TO AGE AT MENOPAUSE

(99% CI)

P value

(99% CI)

Never

4593

1344

(91.9)

3249

(89.0)

1.00b

Ever

418

119

(8.1)

299

(8.2)

0.96 (0.72–1.29)

Missing

102

0

(0.0)

102

(2.8)

—

—

No

4503

1195

(81.7)

3308

(90.6)

1.00b

1.00b

Yes

610

268

(18.3)

342

(9.4)

No

4849

1297

(88.7)

3552

(97.3)

Yes

264

166

(11.3)

98

(2.7)

No

3082

549

(37.5)

2533

(69.4)

1.00b

Yes

2031

914

(62.5)

1117

(30.6)

3.78 (3.20–4.46)

1.00b

P value

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

.733

0.67 (0.49–0.92)

.001

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

TUBAL STERILIZATION ................................................................................................................................................................................................................................................................................................................................................................................

2.17 (1.73–2.72)

⬍ .001

1.38 (1.07–1.78)

.001

................................................................................................................................................................................................................................................................................................................................................................................

ENDOMETRIOSIS 1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

4.64 (3.31–6.51)

⬍ .001

3.44 (2.36–5.01)

⬍ .001

................................................................................................................................................................................................................................................................................................................................................................................

MENORRHAGIA 1.00b

................................................................................................................................................................................................................................................................................................................................................................................

⬍ .001

3.17 (2.64–3.81)

⬍ .001

................................................................................................................................................................................................................................................................................................................................................................................

PAINFUL MENSTRUATION No

4620

1217

(83.2)

3403

(93.2)

Yes

493

246

(16.8)

247

(6.8)

No

4997

1422

(97.2)

3575

(97.9)

Yes

116

41

(2.8)

75

(2.1)

No

4985

1430

(97.7)

3555

(97.4)

Yes

128

33

(2.2)

95

(2.6)

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

2.79 (2.17–3.57)

⬍.001

1.78 (1.35–2.35)

⬍ .001

................................................................................................................................................................................................................................................................................................................................................................................

RECORD OF CANCER 1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

1.37 (0.83–2.28)

.106

1.14 (0.66–2.00)

.537

................................................................................................................................................................................................................................................................................................................................................................................

DIABETES 1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

0.86 (0.51–1.46)

.473

1.20 (0.67–2.15)

.431

................................................................................................................................................................................................................................................................................................................................................................................

RHEUMATOID ARTHRITIS No

4993

1428

(97.6)

3565

(97.7)

Yes

120

35

(2.4)

86

(2.3)

5077

1450

(99.1)

3627

(99.4)

36

13

(0.9)

23

(0.6)

No

4788

1384

(94.6)

3404

(93.3)

Yes

325

79

(5.4)

246

(6.7)

1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

1.03 (0.61–1.74)

.892

1.21 (0.68–2.17)

.395

................................................................................................................................................................................................................................................................................................................................................................................

INFLAMMATORY BOWEL DISEASE No

1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

Yes

1.41 (0.58–3.47)

.320

1.80 (0.67–4.88)

.127

................................................................................................................................................................................................................................................................................................................................................................................

THYROID DISEASE 1.00b

1.00b

................................................................................................................................................................................................................................................................................................................................................................................

0.79 (0.56–1.11)

.077

0.88 (0.60–1.28)

.379

................................................................................................................................................................................................................................................................................................................................................................................

P values calculated using binary logistic regression. CI, confidence interval; OR, odds ratio; RCGP OCS, Royal College of General Practitioners’ Oral Contraception Study. a

Adjusted for age in 1995, social class, pack-years of smoking, and oral contraceptive use up to age at menopause, except where that particular variable was examined; b Referent.

Pokoradi. Risk factors for age and type of menopause. Am J Obstet Gynecol 2011.

Our results relied on respondents recalling their age at menopause, an event that for some women may have been many years before. However, self-reported re-

productive history, including age at natural menopause, has been shown to be recalled with good accuracy.27 The very long-term nature of our study means that

it may have been subjected to changes over time, such as in the economic, social, and medical care environment. Despite this, no birth cohort effect was observed for age at

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General Gynecology

menopause in respondents with a natural menopause.

Characteristics of women with natural menopause Unlike other studies,15,17 we identified no association between manual social class and age at natural menopause. This is consistent with the National Survey of Health and Development, which also found no relationship between social class and age at natural menopause in their United Kingdom cohort.19 In our study, cigarette smoking was significantly associated with early natural menopause. Similarly, the Massachusetts Women’s Health Study found that current smokers reached menopause at a significantly younger age than nonsmokers.26 The National Survey of Health and Development found that current smoking at age 36 years was associated with significantly increased risk of reaching menopause earlier than nonsmokers.28 These findings support the hypothesis that cigarette smoking is cytotoxic to the ovaries, leading to premature menopause.29,30 We found no association between BMI at age 30 years and early natural menopause. This is consistent with results from the National Survey of Health and Development, which examined the association between BMI at age 36 years and early natural menopause.28 Reproductive, gynecological, and other medical history, and natural menopause It is known that OC use and pregnancy disrupt the ovulation cycle. Whether this contributes to a later age at natural menopause is disputed. We found that ever-use of OC was significantly associated with early rather than later natural menopause. We have no obvious explanation for this finding, thus it is important that others investigate this. A Dutch cohort study found that ever-users of OC had a significantly later natural menopause than never-users (mean 51.2 years, SD 3.29 vs 50.1 years, SD 4.16; P ⬍ .01).15 In contrast to these findings, the Massachusetts Women’s Health Study did not find an association between everuse or duration of OC use and age at menopause.7 34.e11

In the RCGP OCS, women who experienced early natural menopause were significantly less likely to have ever used HRT beforehand than women with later natural menopause. This may be explained by the fact that some women will have used HRT in the perimenopausal period, making it difficult to know when FMP occurred. Since most women will have regular bleeding with HRT, some women may be reporting a later FMP than they might have done if they had not used HRT. No literature was identified that considered tubal sterilization or endometriosis in relation to onset of natural menopause, although Visvanathan and Wyshak31 postulated that ovarian function may decline after sterilization due to postsurgery necrosis of the ovarian arteries. Contrary to Dorman et al,11 we did not find that diabetic women had an earlier age at menopause than nondiabetic women. The small number of diabetic women in our study, however, may have reduced its statistical power to detect an important effect. Neither did we find any relationships between other autoimmune conditions (ie, rheumatoid arthritis, inflammatory bowel disease, and thyroid disease) and early natural menopause, although relatively few women in our study sample had a history of these conditions.

Characteristics of women with surgical menopause Many studies examining factors associated with age at menopause exclude women who experienced surgical menopause from their analyses. Identifying any associations between different factors and surgical menopause is important because women who experience a surgical menopause may be at risk of severe menopausal symptoms and future ill health.32 The RCGP OCS had a high proportion (28.6%) of postmenopausal women who were classified as having had a surgical menopause. These women were more likely to be of manual social class than nonmanual social class. The Oxford Family Planning Association contraceptive cohort study,33 which has followed 17,032 British women prospectively from 1968, found no relationship be-

American Journal of Obstetrics & Gynecology JULY 2011

www.AJOG.org tween manual social class and surgical menopause. A Danish cohort study found that women of lower social class had twice the chance of hysterectomy as those of the higher social class, although this was not statistically significant.34 Neither the RCGP OCS, nor an Irish study of the prevalence of hysterectomy, found an association between smoking and surgical menopause.35 BMI at age 30 years was not associated with a strong pattern of risk of surgical menopause in our study, similar to a Danish cohort study assessing weight at age 35 years and subsequent hysterectomy.36 A US cross-sectional study found a significantly higher proportion of hysterectomy among white women whose BMI was ⱖ30 kg/m2 than those whose BMI was ⬍30 kg/m2, but not a significantly increased relative risk of hysterectomy in the heavier group on multivariate analysis.37

Reproductive, gynecological, and other medical history, and surgical menopause Our study found no association between OC use and surgical menopause after adjustment. A cross-sectional Danish study found an inconsistent pattern of risk of hysterectomy among women who used OC for different lengths of time.38 The abrupt drop in endogenous estrogen levels caused by hysterectomy can lead to severe menopausal symptoms,32 and to remedy this, HRT is frequently prescribed. The lower likelihood of use of HRT before hysterectomy reflects the fact that most women have this operation at a young age when menopausal problems are not apparent. Tubal sterilization was associated with increased likelihood of surgical menopause. A prospective case-control study of Scottish women found that sterilized women had ⬎3 times the rate of subsequent hysterectomy than nonsterilized women.39 A multiethnic US case-control study found similar results to the RCGP OCS: sterilized women had a 35% increased risk of subsequent hysterectomy in 7 years of follow-up than nonsterilized women.40 It is likely that some of the reproductive and gynecological conditions (ie, en-

General Gynecology

www.AJOG.org dometriosis, menorrhagia, and painful menstruation) examined were indications for hysterectomy and hence surgically induced menopause. Fibroids, menstrual disturbances, prolapse, cancer, and endometriosis were identified as indications and factors associated with hysterectomy in the Oxford Family Planning study.33 In a US study that examined prevalence of hysterectomy and bilateral oophorectomy in diabetic women, their nondiabetic sisters, and nondiabetic control subjects, no association was found between diabetic status and either hysterectomy or bilateral oophorectomy.11 A similar absence of effect was seen in our study although the number of diabetic women was small. Autoimmune thyroid disease may account for many cases of premature ovarian failure (menopause occurring ⬍40 years).41 We found no association between thyroid disease and surgical menopause. In a small case-control study conducted in Cardiff, Wales, women affected with Hashimoto’s thyroiditis were 4 times more likely to have a hysterectomy than unaffected women.42 While some of the associations with early natural menopause or surgical menopause were comparable to other studies, some new relationships were identified, such as an increased likelihood of early natural menopause in contraceptive pill users and women who had undergone tubal sterilization. More associations were identified in the surgical menopause than early natural menopause analysis. This is important for clinical practice and public health because it suggests that women with surgical menopause may have poorer health before the event than women experiencing an earlier natural menopause. Since some of the associations have not been reported before in United Kingdom women, it will be important to try to confirm or refute our findings in other population-based, representative samples of United Kingdom women. f ACKNOWLEDGMENTS We thank Prof Amanda Lee and the medical statistics team at the University of Aberdeen and Data Management Services for their expert

advice. We also thank the 1400 recruiting GPs and the thousands of women who participated in the health survey.

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