Do early life factors influence the timing of the end of reproductive life?

Anna Murray
1
(a.murray@exeter.ac.uk), Katherine S. Ruth
1
, John R.B. Perry
1,2
, David Melzer
3
, Mike Weedon
1
1
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom;
2
MRC Epidemiology Unit, University of Cambridge,
Cambridge CB2 0QQ;
3
Epidemiology and Public Health, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
Introduction
Menopause occurs when the number off oocytes in the ovary are reduced
below a threshold (Figure 1), but the factors that determine the timing of this
event are poorly understood (Figure 2).
Aims of this study:
Test whether early life events alter the timing of the end of reproductive life
Determine the influence of early menopause on risk of disease subsequently
Discussion
Early life exposures, which affect the intra-uterine environment may have an impact on oocyte reserve and thus influence the timing of menopause.
The association between breast cancer risk and menopause is thought to be due to length of oestrogen exposure over reproductive lifespan, ie. later menopause leads
to increased risk of breast cancer. Our data suggests that early onset breast cancer may have a different aetiology, perhaps an increased genetic risk predisposition,
which causes early menopause in addition to breast cancer risk, as is known to be the case for the breast cancer associated gene, BRCA1.
Methods
We analysed data from >250,000 women from the UKBiobank to evaluate the
association between >200 risk factors and the timing of menopause, plus >400
health related outcomes:
Anthropometric height, weight, BMD, pregnancies, birth weight, age at
death etc.
Smoking status, amount, type, passive smoking etc.
Alcohol status, frequency, types, amount etc.
Diet foods eaten, vitamins, supplements, tea, coffee etc.
Lifestyle means of travel, accommodation, deprivation, TV, driving etc.
Health illnesses, medications, status, age, operations, etc.
Cancer self reported cancers, cancer registry data etc.
We assessed menopause in three ways:
1. Natural menopause as a quantitative trait in linear regression models.
2. Cox proportional hazards model of menopause to include premenopausal
and unnatural menopause cases.
3. Case control analysis of early menopause (20-44 years)
Covariates:
We adjusted our models in two ways: with minimal adjustment (ethnicity, social
deprivation, BMI, smoking, age) and extensive adjustment (... plus, pack-years,
alcohol intake, live births, educational level, eats meat)
Results
To account for multiple testing, we chose a significance threshold of 1x10
-5
.
Many of the recognised risk factors and health outcomes were associated with
menopause age as expected, eg. smoking, BMI and osteoporosis.
Early life events such as birthweight, being a twin, age at menarche and maternal
smoking were associated with timing of menopause (Table 1, Figure 3).
Contrary to published reports, earlier menopause was associated with increased
risk of breast cancer.
Stratified analysis revealed the breast cancer association was driven by a strong
association between early menopause and young-onset breast cancer (Figure 4)
Earlier menopause was protective for late onset breast cancer.
Outcomes not associated with age at menopause included: Type 1 and type 2
diabetes, early death, asthma, stroke, heart disease, DVT and infertility.
Figure 1. Oocyte
undergoing second meiotic
division and ovarian decline
(Lambalka, et al. (2009),
Maturitas, 63, 280-291)
Figure 3. Risk factors having a significant effect on menopause age in 6 (bold text) or
5 models. Data shown for cox proportional hazard, fully adjusted model only.
Figure 4. Odds of breast cancer for increasing age at menopause, stratified by
age at breast cancer diagnosis.
FOXL2,
FSHR
FMR1
Smoking
18 common gene variants
Earlier menopause
Osteoporosis
Cardiovascular disease
Type 1 Diabetes
Type 2 Diabetes
Cognitive function
Later Menopause
Breast cancer
Ovarian cancer
Endometrial cancer
Figure 2. Risk factors and outcomes associated with age at menopause
RISK FACTORS FOR EARLIER MENOPAUSE
Risk factor 1. Natural
menopause
(min adjust)
1. Natural
menopause
(full adjust)
2. Cox model

(min adjust)
2. Cox model

(full adjust)
3. Odds ratio
of EM
(min adjust)
3. Odds ratio
of EM
(full adjust)
Maternal smoking 2.01E-12 2.20E-06 2.80E-05 1.29E-02 5.13E-09 1.76E-04
Birthweight 1.20E-11 5.34E-09 3.80E-06 6.58E-05 1.47E-13 8.70E-10
Being a twin 1.64E-09 2.81E-07 1.16E-07 4.33E-06 3.81E-10 3.58E-09
Year of birth 0.00E+00 0.00E+00 5.89E-08 9.72E-07 8.21E-04 6.99E-02
Breast fed 1.67E-11 1.72E-07 3.79E-01 3.05E-01 3.53E-06 3.71E-04
Age at menarche 3.09E-07 4.05E-09 1.27E-10 2.16E-10 2.06E-04 5.87E-06
Age 10 body size 1.54E-09 1.45E-05 1.28E-01 2.35E-01 4.28E-10 1.12E-06
Age 10 height 2.71E-01 4.04E-02 7.47E-01 7.88E-01 3.00E-01 1.04E-01

Table 1. Association p values for early life risk factors on age at menopause.
This research has been conducted using the UK Biobank Resource http://www.ukbiobank.ac.uk/.