Human Reproduction Vol.16, No.8 pp. 1657–1662, 2001

Oral contraceptive use in relation to age at menopause in the DOM cohort E.de Vries1,2, I.den Tonkelaar1,2,4, P.A.H.van Noord2, Y.T.van der Schouw2, E.R.te Velde3 and P.H.M.Peeters2 1International

Health Foundation, Utrecht, 3526 KS, 2Julius Center for Patient Oriented Research, and 3Department of Obstetrics and Gynaecology, University Medical Centre, Utrecht, 3508 GA, The Netherlands 4To

whom correspondence should be addressed at: International Health Foundation, Europalaan 506, 3526 KS Utrecht, The Netherlands. E-mail: [email protected]

BACKGROUND: We investigated the hypothesis that long-term use of oral contraceptives (OCs), in particular high-dose OCs, could postpone age at menopause. METHODS: Data was used from 8701 women who participated in a breast cancer screening programme in Utrecht (DOM-3 cohort), and who did not use hormone replacement therapy (HRT) or OCs in the 4 years prior to their last menses. Data on OC-use, menopausal status, age at menopause, year of birth, parity, smoking behaviour, socio-economic status, body mass index and age at menarche was available. Use of high-dose OCs has been defined in this study as OC-use before 1972. The data was analysed by means of linear regression and Cox’s proportional hazards analysis. Women still menstruating, women with surgical menopause and women lost to follow-up were censored at their last known date of menstruation. Endpoint was the natural menopause (n ⍧ 4589). RESULTS: The use of high-dose OCs advanced the onset of menopause by ∼1.2 months for every year of OC-use compared with no OC-use. High-dose OC-use for ≥3 years, adjusted for confounding variables, increased the risk of earlier menopause compared with no OC-use (adjusted hazard ratio 1.12; 95% CI 1.03–1.21). The use of lower dose OCs did not increase the risk of earlier menopause (adjusted hazard ratio 1.00; 95% CI 0.91–1.09). CONCLUSIONS: These results are inconsistent with the hypothesis that long-term use of OCs could postpone the onset of menopause by inhibiting follicle depletion. Possible explanations are discussed. Key words: cohort study/follicular depletion/menopause/oral contraceptive/risk factors

Introduction The age at menopause is likely to be a retrospective marker of the end of the fertile lifespan of women (te Velde et al., 1998a). The factors that influence age at menopause are therefore also likely to determine the age at which preceding reproductive events occur, such as the beginning of subfertility and the end of fertility. According to Richardson (1993), the transition from regular menstruation to the peri-menopause, with irregular cycles, and the subsequent transition to menopause are mainly determined by the size of the residual follicle pool (Richardson, 1993). The size of the follicle pool is determined by the woman’s initial number of oocytes, and by the rate at which these oocytes are lost. It is generally accepted that FSH has a predominant role in the late stages of follicular development (Gougeon, 1996; te Velde et al., 1998b). It is still a matter of debate whether high FSH concentrations accelerate the depletion of the follicle pool, by stimulating resting follicles to start growing (Kumar et al., 1997; Dierich et al., 1998; te Velde et al., 1998b; Parrott and Skinner, 1999). However, there is sufficient epidemiological evidence © European Society of Human Reproduction and Embryology

to suggest that low or suppressed FSH concentrations are associated with delayed age at menopause (Stanford et al., 1987; Cramer et al., 1995b; Sowers and La Pietra, 1995; Kato et al., 1998; Hardy and Kuh, 1999). Since OCs also suppress FSH concentrations, long lasting use of OC may also delay age at menopause. The few studies that included the effect of OC use in their design found either a delaying effect of OC use on age at menopause (Van Keep et al., 1979; Stanford et al., 1987) or no effect (Brambilla and McKinlay, 1989; Cramer et al., 1995b; Bromberger et al., 1997; Van Noord et al., 1997). However, most studies failed to exclude women who used hormone replacement therapy (HRT) or OCs for menopausal complaints, leading to a potentially spurious positive association between OC use and menopausal age. Studies addressing the relationship between the use of high dose OCs and menopausal age are lacking. High dose OCs strongly suppress FSH concentrations because of their high doses of oestrogens and progestins. Other types of OCs contain lower doses of oestrogens and progestins, suppressing FSH in a more moderate way. Therefore, particularly in the case of 1657

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high dose OC use, one can expect a delay in menopausal age. If it can be confirmed that use of high dose OCs delays age at menopause it is also likely that use of high dose OCs delays the end of fertility. If lower dose OCs also have a delaying effect on menopause, this could be a promising perspective for women who postpone their first pregnancy until their thirties by means of OC use. In this cohort study, we investigated the effect of OC use on menopausal age. We were able to use a cohort of a large number of women (n ⫽ 8701), 3242 of whom reported that they used high dose OCs.

Materials and methods Population From January 1982 to April 1985 all women born between 1932 and 1941 and living in Utrecht or one of the 22 smaller municipalities in the province of Utrecht, The Netherlands, were invited to participate in a breast cancer screening programme (de Waard et al., 1984). Of these women 12178 women participated and they became known as the DOM-3 cohort. (DOM is short for ‘Doorlopend Onderzoek Morbiditeit/Mortaliteit’). The women filled out a self-administered questionnaire on medical history, use of OCs, use of HRT for menopausal symptoms, smoking, reproductive history, menopausal status, age at menopause, surgery that caused cessation of menses, and health insurance. The women were asked to mark on a calendar the years in which they had used OCs for at least 3 months. Women were defined as being post-menopausal if their menses had been absent for at least 12 months due to factors other than pregnancy or lactation; all of the other women were defined as premenopausal. Women who were still considered pre-menopausal at their initial screening visit were sent a postal questionnaire in 1986, comprising questions about the date of their previous menstrual period and the use of HRT or OCs for menopausal symptoms during the past 4 years. If women had undergone a medical treatment that caused cessation of menstruation, they were asked what kind of treatment this was. They were also asked to keep their menstrual data on a calendar sent along with the questionnaire. Women who were still pre-menopausal were sent a similar questionnaire in 1987, 1989, 1992, 1993 and 1995. Response was about 80% each year. Both women who responded and those who did not respond in early 1986 were sent a questionnaire in late 1987. But women not responding in 1987, 1989 and 1991 were not sent a questionnaire in 1989, 1991 and 1993 respectively. We made special efforts to complete the follow-up for a random sub-sample of 4207 women in 1992. We found the new addresses of women who had moved via municipal administrations. All women who had failed to respond to one of the previous questionnaires were sent a questionnaire again and those still not responding were approached by telephone. After these efforts follow-up for this subsample was 90% complete. For the total cohort the follow-up is 82% complete. Menopausal age The date of menopause was the last date of menses, defined retrospectively following 12 months of amenorrhoea. Age at menopause was computed by subtracting the date of birth from the date of the onset of menopause. For women who were post-menopausal at their screening visit (n ⫽ 1076), the exact date of menopause was not known. The questionnaire filled out at screening provided data on menopausal age (in years), not the exact date (day, month, year) of their last menstruation. Therefore, only truncated menopausal ages

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are known for these women. We decided to truncate the menopausal ages of all the women to standardize them. OC use OC use is characterized as ‘ever use of OCs’, ‘duration of use’, and ‘duration of use of high dose OCs’. Ever use was defined as OC use for at least 3 months. Duration of OC use was defined as the sum of years in which a woman used OCs for at least 3 months. In The Netherlands, the first tablets containing oestrogens and progestins (lynestrenol) were introduced in 1962, officially only for treatment of disturbances of the menstrual cycle. Based on market information it was estimated that in the Utrecht region prior to 1972, high dose (⬎50 µg oestrogen) OCs were predominantly prescribed (Haspels and Kay, 1982). Duration of high dose OC use was defined as the sum of years before 1972 in which a woman used OCs for at least 3 months (van Hoften et al., 2000). Exclusion and inclusion criteria Subjects who used HRT or OCs for menopausal symptoms during the 4 years prior to the date of last menstruation or the first year following the last menstruation (n ⫽ 3477) were excluded from the analyses, because these women can have withdrawal bleedings caused by the use of OCs or HRT, obscuring the date of the menopause. Of the women included in the analyses (n ⫽ 8701), age at natural menopause was known in 4523 cases (1076 of whom were postmenopausal at their initial screening visit), 4178 women were censored at the age of their last known menstruation because they did not experience a natural menopause. Of these censored women, 2466 women had undergone surgery that caused cessation of menstruation, 1547 were still pre-menopausal when they were lost to follow-up and 165 women were pre-menopausal in the questionnaire from 1995. Confounders Smoking, parity, body mass index (BMI), socio-economic status and possibly age at menarche are related to menopausal age, and were therefore considered as potential confounding variables. Current smoking was defined as having smoked cigarettes regularly during the past year and past smoking was defined as having smoked more than a year ago. Socio-economic status is based on the type of health insurance, whether public health insurance, which is government mandated (lower status), civil servants insurance (intermediate status) or private insurance (higher status). Trained medical assistants measured height and weight at the screening. BMI was calculated using the formula [weight (kg)/height (m)2]. The year of birth was also included in the analyses to check for any discrepancies in variable characteristics among the different age groups. Statistical analyses Kaplan–Meier estimates were used to compare failure time distributions for the categories in each risk factor. Log-rank tests were carried out to test the differences in failure time distributions. The endpoint of the analyses was natural menopause (failure). Cessation of menstruation due to other causes and loss to follow-up were censoring events. The biological age of the participating women was on the time axis. To obtain estimates of the hazard ratio (HR) for each variable and for each variable adjusted for all potential confounders we used Cox’s proportional hazard models. These models predict the ratio of incidence rates as the dependent variable: the hazard ratio. This ratio is assumed to be constant over time (proportional hazards) (Rothman, 1986). This assumption of proportional hazards was checked for each variable by making log-minus-log plots. The assumption was found to be justified for all variables.

Oral contraceptives and age at menopause

Table I. Results of log-rank tests for the comparison of the Kaplan–Meier survival functions and the unadjusted hazard ratios.

Types of OC use Never used OC Only lower dose OC 1–2 years high dose OCa 艌3 years high dose OCa Total years of OC useb Never used OC 1–2 years 3–5 years 6–10 years 艌11 years Parity No children 1–2 children 3 or more children Smoking Never Past Current smoker BMI BMI 艌27 BMI ⬎27 Health insurance Public health Civil servant Private Year of birth 1932–1934 1935–1938 1939–1941

Number of women (Total n ⫽ 8701)

Average age at menopause

P value log-rank-test

Unadjusted HR (95% CI)

4185 1274 1398 1844

(50.9) (51.0) (51.0) (50.7)

0.12

1 0.96 (0.88–1.05) 0.99 (0.90–1.07) 1.07 (0.99–1.15)

4185 1296 1126 1249 845

(50.9) (51.2) (50.8) (50.8) (50.6)

0.05

1 0.93 1.03 1.02 1.10

1126 3961 3614

(50.1) (50.8) (51.2)

⬍ 0.001

1 0.84 (0.77–0.92) 0.77 (0.71–0.85)

4618 1279 2804

(51.2) (51.2) (50.0)

⬍ 0.001

1 1.02 (0.93–1.11) 1.36 (1.27–1.45)

6715 1986

(50.8) (51.2)

⬍ 0.001

1 0.88 (0.82–0.95)

5338 965 2395

(50.7) (51.1) (51.2)

⬍ 0.001

1 0.90 (0.82–0.99) 0.89 (0.83–0.95)

2737 3400 2564

(50.7) (50.8) (51.0)

⬍ 0.001

1 0.96 (0.90–1.03) 0.84 (0.78–0.91)

(0.85–1.02) (0.94–1.13) (0.93–1.11) (0.99–1.22)

aThese

women used high dose OCs for the given number of years, but it is possible that they also used lower dose OCs. bHigh and lower dose together.

An HR ⬍1 indicates a decreased risk for an event. In our analyses, this means a decreased risk of entering menopause, meaning a decreased risk of menopause at any given age. An HR ⬎1 indicates an increased risk of entering menopause. Tests for trend were calculated by polynomial contrasts. To further quantify the effect of OC use on menopausal age, linear regression analyses were performed on the group of women with a natural menopause (n ⫽ 4523).

Results The overall estimated median age at menopause is 51 years (average 50.82). From the Kaplan–Meier estimates, there is no clear indication that OC use influences menopausal age. There is evidence of a difference in menopausal age due to parity, smoking, BMI, type of health insurance and year of birth, as indicated by the log-rank tests (Table I). Duration of use of high dose OCs for 3 or more years and a total use of 11 or more years of any type of OC does not significantly influence age at menopause (unadjusted HR ⫽ 1.07; 95% CI 0.99–1.15 and HR ⫽ 1.10; 95% CI 0.99–1.22 respectively, Table I). Table II shows adjusted hazard ratio’s for risk factors included in the study. After taking into account all other risk factors, the long-term (艌3 years) use of high dose OCs and

long-term (艌11 years) overall OC use were proven to have a significant association with an earlier age at menopause (adjusted HR ⫽ 1.12; 95% CI 1.03–1.21 and HR ⫽ 1.13; 95% CI 1.02–1.25 respectively, Table II). The use of lower dose OCs had no influence on menopausal age. Nulliparous women are more likely to enter menopause at an earlier age than parous women since parous women have a lower HR of entering menopause than nulliparous women. The more children a woman has given birth to, the later she will enter menopause. Women who currently smoke will reach menopause at an earlier age than women who have never smoked or used to smoke. Women with a BMI 艋27 will reach menopause earlier than women with a BMI ⬎27 and women with a low socio-economic status will experience an earlier menopause than women with a higher socio-economic status. The younger birth cohort of women has a decreased risk of entering menopause compared with the older birth cohorts in this study. In our data, age at menarche was not associated with age at menopause and, as expected, was also not a confounder in the association between OC use and menopausal age (data not shown). Therefore, age at menarche was not included in the final analyses. The linear regression analyses show that for each year of high dose OC use, age at menopause decreased by 1.2 months (P ⬍ 0.001). 1659

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Table II. Adjusted hazard ratios (HR) for all risk factors included in the model.

Types of OC use Never used OC Only lower dose OC 1–2 years high dose OCc 艌3 years high dose OCc Total years of OC used Never used OC 1–2 years 3–5 years 6–10 years 艌11 years Parity No children 1–2 children 3 or more children Smoking Never Past Current smoker BMI BMI 艌27 BMI ⬎27 Health insurance Public health Civil servant Private Year of birth 1932–1934 1935–1938 1939–1941

No. of women

Adjusted HRa (95% conf. interval)

Adjusted HRb (95% conf. interval)

P value

4185 1274 1398 1844

1 1.00 (0.91–1.09) 1.05 (0.96–1.15) 1.12 (1.03–1.21)

-

⬍ 0.005

4185 1296 1126 1249 845

-

1 0.98 1.08 1.08 1.13

1126 3961 3614

1 0.85 (0.77–0.93) 0.77 (0.70–0.84)

1 0.85 (0.78–0.93) 0.77 (0.70–0.85)

4618 1279 2804

1 0.99 (0.91–1.08) 1.32 (1.24–1.42)

1 0.99 (0.91–1.08) 1.32 (1.24–1.41)

6715 1986

1 0.87 (0.81–0.93)

1 0.86 (0.81–0.93)

5338 965 2395

1 0.91 (0.83–1.00) 0.90 (0.85–0.97)

1 0.91 (0.83–1.00) 0.91 (0.85–0.97)

2737 3400 2564

1 0.94 (0.88–1.01) 0.81 (0.75–0.88)

1 0.94 (0.88–1.01) 0.81 (0.75–0.88)

⬍ 0.005 (0.90–1.07) (0.98–1.18) (0.98–1.18) (1.02–1.25)

aThis model includes parity, smoking, BMI, health insurance, year of birth and years of OC use before 1972. bThis model includes parity, smoking, BMI, health insurance, year of birth and total years of OC use. cThese women used high dose OCs for the given number of years, but it is possible that they also used

lower dose OCs. and lower dose together.

dHigh

Tests for trend showed the existence of a significant linear trend for years of high dose OC use (P ⬍ 0.005) and total years of OC use (P ⬍ 0.005) with menopausal age. Discussion Before interpreting the results of this study, some issues need to be addressed. The excluded group of women (women who used OCs or HRT around the date of their last menstruation) (n ⫽ 3477) did not differ from the included group with respect to most of the variables, except that they generally had a later self-reported menopause, as expected. The excluded women were also somewhat younger and had had fewer hysterectomies and/or ovariectomies. Quite a few women were lost to follow up (n ⫽ 1547). Although we cannot exclude the possibility of selective loss to follow-up, this seems unlikely as this group of women does not differ in the distribution of variables other than that they were generally younger than the other women. It is possible that the effect of high dose OCs is due to the fact that in The Netherlands, from 1962–1969, OCs were officially only registered to treat disturbances of the menstrual cycle and not for contraceptive purposes. Therefore, it is possible that women who used high dose OCs were pre1660

dominantly women with signs of early ovarian ageing (irregularity of cycles). These women were expected to enter menopause at an earlier age than women without signs of early ovarian ageing. However, as women who used OCs in the 4 years prior to menopause were excluded from our analyses, we find it unlikely that such a selection will have substantially influenced our results. In addition, it is very likely that physicians often prescribed these OCs for contraceptive purposes, despite the fact that this was officially prohibited until 1969. The population-based design of our study is an advantage, as we did not examine a selected group of women. We were able to collect data from a large number of women (n ⫽ 8701), making it easier to find subtle effects of potential risk factors on menopause. Our cut-off point for high dose OC use is somewhat arbitrary. Before 1972, lower dose OCs were already being prescribed and after 1972, some women were still using high dose OCs. Different manufacturers introduced new types of OCs throughout the years and used different doses and types of oestrogens and progestins in their products. The possibility of mis-classification of women using high dose OCs is present. We were obliged to use this cut-off point because the individual data about the type of OC women used is not known. By

Oral contraceptives and age at menopause

using the market information we were able to estimate the effect of long-term use of high dose OCs, despite the fact that the individual data was missing. In this study, the date of menopause for most women was determined prospectively (n ⫽ 3447). Relatively few women were already menopausal at their screening visit (n ⫽ 1076). For these women age at menopause was determined retrospectively. However, the date of their last menstruation was relatively recent, reducing the possibility of recall errors. We confirmed all known effects for the other variables included in our analyses (Sowers and La Pietra, 1995; Kato et al., 1998; Hardy and Kuh, 1999). This point is reassuring regarding the validity of our study. Although we adjusted for possible confounders, the possibility of residual confounding by smoking and socio-economic status cannot be excluded. Our main finding is that long-term users of high dose OCs (⬎50 µg oestrogen for 3 or more years) experience menopause at a slightly younger age compared with women who did not use OCs or only used lower dose OCs (艋50 µg oestrogen). Use of lower dose OCs has no influence on age at menopause. Eleven or more years of total OC use advanced menopausal age. However, this is probably due to the effect of long-term use of high dose OCs. Our results are in contradiction with the results of most other studies investigating the influence of OCs on menopausal age. These studies either found no effect on menopausal age (Brambilla and McKinlay, 1989; Cramer et al., 1995b; Bromberger et al., 1997; Van Noord et al., 1997) or a postponement of menopause with OC use (Van Keep et al., 1979; Stanford et al., 1987). An investigation into the influence of OC use on peri-menopausal age, indicated the existence of a (nonsignificant) trend for earlier inception of peri-menopause with long-term OC use (Hardy and Kuh, 1999). This result is consistent with our findings. The majority of studies, with the exception of just two (Bromberger et al., 1997; Hardy and Kuh, 1999), did not exclude women who used HRT or OC for menopausal symptoms from their analysis. In our study we have excluded this group of women, because dates of natural menopause can be obscured by bleedings caused by OC use or use of HRT. None of the studies mentioned made a distinction between different types of OCs or took into account a dose-response relation. Some studies did not adjust for other variables influencing menopausal age, such as smoking and parity. Our univariate results also showed no effect of OC use; the effect of OCs became apparent only after adjustment for other variables. As in previous reports, parity and a high BMI increased age at menopause, whilst smoking decreased age at menopause (Cramer et al., 1995a,b; Sowers and La Pietra, 1995; Kato et al., 1998; Nagata et al., 1998; Hardy and Kuh, 1999). We have found a decreased risk of menopause in the cohorts of younger women. This is probably due to an age-related artefact: these cohorts simply have not yet had the same chance of being menopausal as the cohort of older women in this study. The predominant role of FSH in the late stages of follicular development is extensively investigated and generally accepted (Gougeon, 1996). In contrast, the reason why follicles start to grow after many years of dormancy is still a mystery.

Experimental findings and observations clearly show that follicles are able to grow without the presence of gonadotrophins (Kumar et al., 1997; Dierich et al., 1998; Parrott and Skinner, 1999). It is understandable therefore, that follicle growth until the selectable stage was considered to be a gonadotrophin-independent process (Wandji et al., 1997). However, there is growing evidence indicating that in complex cooperation with other factors, FSH facilitates the initiation of follicular growth and stimulates early follicular development (te Velde et al., 1998b). Moreover, there is strong evidence that the actual resting follicle pool does not only contain primordial follicles but also intermediate and primary follicles (de Bruin et al., 2001). Only thereafter does transition to the rapid growth phase commence. The fact that FSH receptors have been demonstrated in the granulosa cells of primary follicles (Oktay et al., 1997) is in agreement with the possible role of FSH during the transition from the resting follicle pool to the growth phase. Our investigation was based on the hypothesis that menopause can be delayed by sparing resting follicles. If FSH stimulates the initiation of growth of these resting follicles, then this would mean that very low concentrations or the absence of FSH would inhibit this initiation and thereby delay menopause. This hypothesis is partly confirmed by studies in which it was observed that FSH-suppressing factors, such as parity and irregular or long menstrual cycles, can delay age at menopause (Cramer et al., 1995b; Sowers and La Pietra, 1995; Van Noord et al., 1997; Kato et al., 1998; Hardy and Kuh, 1999). OC use suppresses FSH concentrations, therefore it was hypothesized that long-term OC use, in particular long-term high dose OC use, would postpone menopause to a later age. The results of our analyses contradict this hypothesis: longterm use of high dose OCs does not delay menopause, it actually accelerates the onset of menopause. Our finding may be explained by the findings of other studies (Gougeon, 1996) stating that the absence of FSH increases levels of oxidative free radicals in granulosa cells. This in turn causes the activation of endonucleases, thereby initiating apoptosis of follicles. Our findings may also be explained by the fact that exogenous progesterone can have a damaging effect. It was found that mice who had been exposed to exogenous progesterone showed increased atresia of antral follicles (Telfer et al., 1991). In addition, a study on the methods of initiation of primordial follicle development in rats in vitro (Parrott and Skinner, 1999) showed that primordial follicles develop into primary follicles in medium with no factor added. Treatment of ovaries with gonadotrophins inhibits this spontaneous development of primordial follicles into primary follicles. If this is also the case in vivo in humans, OC use could accelerate the depletion of the follicle pool by lowering gonadotrophin concentrations, thereby allowing the spontaneous development of primordial follicles into later stages of follicle development. The fact that we did not observe any effect on menopausal age in lower dose OCs might be explained by the fact that lower doses of oestrogens and progestins suppress FSH concentrations in a more moderate way (Copeland, 1993). In conclusion, the effect of OC use found in this study is 1661

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in contradiction with the hypothesis that long-term OC use delays age at menopause. Our results suggest that long-term use of high dose OCs accelerates menopause and that use of lower dose OCs has no effect on age at menopause, although possible bias by residual confounding cannot be excluded. Acknowledgements The contributions of Mrs Leida Elders and Ms Carlijn van Hoften in collecting data and of Ms Brigitte Hoeve for her assistance with English are greatly appreciated. We also thank Ms Helen Kok and Ms Kristel van Asselt for their advice and support.

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