What does new research into the genetics of the age of menopause reveal? How does this translate to female health in practical terms?
Every woman will reach menopause around middle age. This is when ovarian responsiveness declines to the extent that ovarian hormone production is no longer sufficient for ovulation to occur.
Ovarian function
The natural age of menopause is on average 51, with a range from 45 to 55 years. About 1% of women experience primary premature ovarian insufficiency (POI), which means reduced ovarian function before the age of 40. For a tiny minority, of 0.1%, this occurs under the age of 30. POI may lead to early menopause, occurring between 40 and 45, or premature menopause occurring before 40 years of age. It is important to identify POI promptly, as a drop in ovarian hormones increases the risk of cardiovascular disease, osteoporosis and decline in cognitive function. So, replacing ovarian hormones through hormone replacement therapy (HRT) is important for long term health, especially for those women with POI[1]. Fertility may also be compromised, although the British Menopause Society stresses that, it is only when menopause is reached, that ovarian function completely stops.
What determines age of menopause?
As with the timing of many physiological processes, the natural age of menopause is thought to be determined by both genetic and environmental factors. A recent paper published in Nature[2] describes how clusters of genes can be used to provide a polygenetic score (PGS) which accounts for 10% of the variation in the age of natural menopause (as opposed to medically induced menopause). The impact of each genetic variant ranged from 3.5 weeks to 1.5 years. Whilst the PGS accounted for a very modest 10% variation in natural age of menopause, the top 1% of the PGS range corresponded to a 5-fold increase in POI compared with women with mid-range scores. The authors themselves urge caution in the clinical application of this multi genetic test approach for predicting natural age of menopause, even in those families with a family history of POI.
The PGS as an indicator of increased risk of POI, is not the novel finding of this paper. The authors state that this result is the same as that obtained through a current single gene test. The most interesting part of the research was how these genes influence the age of menopause. These specific genes code for the DNA repair system for the eggs in the ovary.
Incredibly all the eggs in the ovary are “prepared” while the female foetus is in the mother’s uterus during pregnancy. The double stranded DNA in each egg unwinds and is partially split, leaving it literally in suspended animation. These eggs have to wait another 15 to 50 years before being called upon to complete the halving of double stranded DNA. Ultimately an egg has one DNA strand when ovulated during the menstrual cycle, ready to be united with a matching single strand from a sperm. Some eggs never make the cut for ovulation.
As all the eggs were prepared in the ovaries of the female foetus, they all have the same “shelf life”. Over adult life, the shelf on which the eggs are resting metaphorically starts to tip. The DNA repair mechanisms try to keep the shelf level. However, inevitably the shelf tips over at menopause. This shelf life of eggs, contrasts with sperm in men, which are made continuously throughout adult life.
From an evolutionary perspective having a shelf life on eggs and reaching menopause is probably for the benefit of the mother and the potential baby. Although life expectancy has increased, the ageing process is something that none of us can avoid. Pregnancy, childbirth and raising a child are demanding, even more so beyond middle age. From the baby’s point of view, it is well documented that increasing maternal age increases the risk of genetic issues for the embryo. This is where genetic repair mechanisms outlined in the research paper become really important. As the DNA in the eggs in the foetal ovaries are in suspended animation, in a delicate state for the rest of the woman’s life, the DNA repair enzymes need to be on high alert to keep the eggs “fresh” and ready for ovulation.
In experiments on female mice, manipulating the two genes for DNA repair did prolong fertility and for one of these genes, also bolstered the ovarian response to hormone stimulation. However, the downside is that in the latter case this could also increase the risk of cancer. Furthermore, we do not know how manipulating maternal genetics would translate to the genetics of the offspring; nor how this genetic manipulation translates from mice to women.
Ideally it would be helpful to keep a watching brief on all factors contributing to egg health.
The missing link: female hormone networks
The authors state that their paper focused on genetics and did not consider the other key influencers of female health, fertility and definition of menopause: hormones[3]. If genetic factors account for 10% of the variation in the age of menopause, that leaves 90% unexplained. A significant proportion of the variation is likely to be due to environmental factors. Lifestyle and behavioural choices influence hormones and it is hormones that regulate gene expression in DNA.
This means that, whatever your genetic endowment, making good choices around lifestyle factors of nutrition, exercise and sleep, while avoiding negative choices like smoking, certainly helps hormone networks and therefore impacts gene expression.
Ideally a measure of dynamic hormone function would be more informative about transition to menopause. Such an approach is now possible, by combining medical and mathematical expertise through artificial intelligence techniques, giving a real time watching brief on female health. Monitoring over time can track any decline suggesting transition to menopause.
What can we conclude about age of menopause?
- Menopause is a significant physical and psychological event in a woman’s life. Declining ovarian hormones pose challenges for long term health.
- Average age of natural menopause is 51 (range 45-55 years). Early menopause occurs between 40 and 45 years of age and premature menopause under 40. Primary ovarian insufficiency (POI) is where the ovaries start to loose responsiveness before the age of 40.
- The age of menopause is determined through a combination of genetic and environmental factors. A new research genetic test combining various genes can predict up to 10% of the variation in the natural age of menopause, leaving 90% determined by non-genetic factors. In 1% of the outlying genetic scores, this corresponded to an increased likelihood of premature ovarian insufficiency, the same as current single gene test.
- The authors of the research urge cation that this multiple gene test is not a suitable clinical test for women, even for those with family history of POI. Nevertheless, this research sheds light on the DNA repair mechanisms that play a part in determining age of menopause.
- This paper focused on genetics and did not discuss the hormone networks. Menopause is defined as no further menstruation when the ovaries stop producing hormones.
Practical take home points
- You can obtain a free genetic test by asking your female family members about their age of menopause. This also opens up conversations about menopause.
- Premature Ovarian Insufficiency does not definitively exclude the possibility of pregnancy
- For all women, ovarian responsiveness and fertility decline after 40 years, at a variable rate.
- Female hormone networks should be considered and can be assessed as part of the personalised assessment of ovarian function, with medical explanation and evidence based advice.
- For medical doctors, membership of British Menopause Society provides a wealth of resources and specialist training opportunities
It is every woman’s personal choice when and if she wishes to become pregnant. Nevertheless, it is important for women to be aware of their personal female physiology. Genes are passed down through the generations, but the expression of those genes is determined hormone networks. Since lifestyle choices affect hormones, they determine to a large extent how your personal story unfolds.
References
[1] Management of the Menopause. Sixth Edition. British Menopause Society
[2] Ruth, K.S., Day, F.R., Hussain, J. et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature (2021). https://doi.org/10.1038/s41586-021-03779-7
[3] Genomic analysis identifies variants that can predict the timing of menopause. Nature 2021
[4] Keay N. Hormone Intelligence for Female Dancers, Athletes and Exercisers British Journal of Sports Medicine 2021
[5] Keay N Fingerprinting hormones St John’s College Cambridge 2021
Dr Nicky Keay 