Aims and objectives of the programme

Broad aims of programme

The aims of the programme are to (i) understand the mechanisms that underlie the associations of women's reproductive characteristics (age at menarche, menstrual patterns, follicular activity, fertility, pregnancy and age of menopause and menopausal changes) with later risk for chronic complex diseases and their risk factors (obesity, hypertension, dyslipidaemia, hyperglyaceamia, insulin resistance, type 2 diabetes, coronary heart disease, stroke, osteoporosis, depression, breast density and breast cancer); (ii) to understand the role of women's reproductive health in healthy ageing and (iii) to determine the mechanisms for the intergenerational transmission of patterns of women's reproductive, cardiovascular, metabolic, skeletal and mental health.

The programme will bring together existing funded work of the PI and co-applicants that is concerned with pregnancy related changes and future cardiovascular, metabolic and bone health in offspring and mothers (project grants from US NIH, MRC, Wellcome Trust & BHF). In the first phase we will focus primarily on consolidating the work from these different projects (objective 1 of the first 5 years) in order to obtain a comprehensive picture of how pregnancy related changes affect a wide range of future health related outcomes in mother and offspring. In addition in the first 5 years we will obtain detailed repeatedly assessed phenotypic data (hormonal, vascular, metabolic, bone and DNA methylation changes) on a cohort of women (the mothers) as they go through the menopausal transition (from age 47-52 years). These new data will be used to address objectives 2-7 below and will provide the evidence based for understanding how oestrogen deficiency and menopausal changes influence ageing in general and specifically vascular, metabolic and muscular-skeletal ageing. With subsequent renewal of the programme , after the first 5 years, we would focus on the daughter's menstrual pattern, follicular activity and emerging fertility, as well as linking data on the mother's breast density from routine mammography and mental health outcomes to the main dataset.

Specific objectives of the first 5 years

We will:

1. Determine the extent to which pregnancy related weight gain, vascular and metabolic changes are related to the mother's and her offspring's future reproductive, vascular, metabolic and muscular-skeletal health.

2. Determine the pattern of changes in glucose, insulin, lipids, blood pressure, total and truncal fat and bone mineral density as women go through the menopausal transition and distinguish whether there is a specific menopausal effect over and above age related changes in these phenotypes.

3. Determine the hormonal, genetic, molecular and lifestyle pathways that underlie variation in age at menopause and variation in changes in vascular, metabolic and bone phenotypes over the menopausal transition.

4. Determine the association of different patterns of change in glucose, insulin, lipids, blood pressure and total and truncal fat over the menopausal transition with variation in postmenopausal carotid intima media thickness.

5. Establish the role of DNA methylation in determining the timing and magnitude of menopausal changes.

6. Determine the pattern of global and gene-specific (e.g. ESR1) DNA methylation patterns as women go through the menopausal transition.

7. Determine the consequences of menopause- related DNA methylation changes with respect to subsequent changes in vascular, metabolic and muscular-skeletal health.

Data requirements and new data collection

Objective 1 above will use existing data or data currently being collected (e.g. mums clinic and 17+ clinic fasting blood samples and assays) and brings together agreed work of the PIs in ALSPAC as funded by existing grants (NIH; MRC; BHF).

The remaining objectives will be addressed by collection of new data from a subgroup (~3000) of the ALSPAC mothers who fulfil the following criteria:

Age 47-49 years at start of new clinics (September 2010)

No previous history of hysterectomy or bilateral oophorectomy

Not known to have undergone natural menopause

Mothers fulfilling these criteria will be invited to attend annual clinics over a 4 year period (4 clinics in total) at which the following will be completed:

1. Completion of menstrual cycle & hormonal use questionnaire

2. Taking of a fasting blood sample

3. Measurement of weight, height, waist circumference and blood pressure

4. DXA scan - total & hip

The grant will request funds to complete the following on the blood samples:

1. Repeat assessment (at each clinic) of sex hormones, glucose, insulin and lipids

2. Global and gene specific DNA methylation patterns.