Bengaluru: An international team of researchers in Europe have identified genetic variants and markers that can determine the age of natural menopause.
Menopause refers to the natural biological process that marks the end of menstruation and reproductive life in women. Women typically experience menopause in their 40s or 50s, and it is officially diagnosed after 12 months without menses. The unpleasant process is characterised in many women by experiences like hot flashes and mood changes.
For the study, an analysis of over 2,00,000 women of European ancestry revealed 290 genetic variants — or permanent changes in the DNA sequence making up a gene — of ovarian ageing. The researchers noted that the identified variants are involved in a process called DNA damage response (DDR) and are responsible for repairing any damage to DNA. They said that menopause is associated with a loss of function in key genes due to these variants.
Using experimental models, the researchers also manipulated the genes to highlight the role they play over the course of a woman’s life in determining the rate of ovarian production and depletion. Women and all female mammals are born with a fixed number of eggs in the form of oocytes or cells that would go on to become future eggs. Ovaries are not capable of producing new eggs after birth.
The study further showed that some DDR pathways can be genetically manipulated to increase fertility and extend the period of reproductive capability in mice.
While it is still in the early stages, the research offers crucial insights into the ageing process of the female reproductive system, rate of ovarian production and depletion and the genes that govern these processes.
The findings, published in the journal Nature Wednesday, provide new clues that could influence future targeted therapeutic approaches for human fertility.
The authors also noted that the genetic variants that were identified indicated that extending reproductive life in women improved their bone health and lowered the risk of type 2 diabetes. And therefore, the findings could offer pathways for new therapeutic approaches to prevent diseases.
However, the authors warned that increasing reproductive life could raise risk the of hormone-related cancers.
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Manipulation of Chek1 and Chek2 genes in mice
In the study, the authors analysed the genetic data of 2,01,323 women of European descent who had already experienced menopause when they were aged between 40 and 60.
The team studied over 13 million genes and DDR pathways associated with ovarian health and delayed menopause to identify the genetic determinants of ovarian ageing.
Unlike the onset of menstruation at puberty, which is influenced by the genes expressed in the hypothalamus and pituitary gland, menopause was dependent only on genes expressed in the ovaries and reproductive tissues.
The researchers identified two key enzymes — ATR-CHEK1 and ATM-CHEK2 — that perform DNA repair and seemed to affect reproductive period and onset of menopause in women. They then manipulated the associated genes, Chek1 and Chek2, in female mice to observe the effects in their offspring.
When Chek1 was overexpressed (switched on in ageing genes after it is naturally turning off) in the mother mice, her female pups and the generation after that had an increased reproductive life, the study found.
This was possible with an increase in the number of starting oocytes in the foetus. Thus, by increasing the number of oocytes at birth, the gene enabled two generations of mice to have a longer period of reproductive life. The researchers, therefore, also established that the quality of eggs was not compromised genetically despite manipulation.
Meanwhile, when Chek2 was inactivated in mice, the subsequent generations demonstrated an increased reproductive lifespan as well but not from an increase in the egg reserve.
Rather, the gene reduced the natural degradation of follicles in the ovaries, within which oocytes develop into egg cells. This enabled the follicles to function for longer periods of time, producing more egg cells and thus reduced the rate of depletion of eggs, thereby extending reproductive life.
In women who naturally lacked the gene, the age of menopause was an average 3.5 years later than women with an active gene.
The researchers also used other independent datasets to confirm their findings, including 78,317 women of East Asian descent.
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Female health
The field of medicine and public health have made enormous strides in extending the life expectancy in wealthy nations over the last 150 years, but the onset of menopause in these countries has constantly remained in the range of 50-52 years of age, explain the researchers.
As women age, the risk of conceiving a foetus with genetic abnormalities (and a possible subsequent miscarriage) increases because the genetic integrity of female eggs or ova get compromised. Previous studies have also shown that about 10 years before menopause, natural fertility comes to an end in menstruating women.
Increasingly, more and more women are delaying childbearing to older ages, which has resulted in the use of assistive fertility treatments and techniques. Unlike preservation of sperm, preserving eggs and ovarian tissue is an invasive, painful procedure with only a 6 per cent chance of success, and highly dependent on the age of the woman.
According to the researchers, since inactivating Chek2 results in improved ovarian function as eggs last longer, it could be a potential therapeutic target for women undergoing in vitro fertilisation or IVF treatment.
The team also confirmed that delaying menopause genetically aided bone mineral density, reduced risk of fracture in bones and lowered risk of type 2 diabetes. They stated that their findings are consistent with previous oestrogen therapy studies that have shown benefit to bone health and protection against diabetes.
Other studies have also demonstrated that hormone therapy does not increase risk of cardiovascular disease or death in women. The researchers confirmed that they too did not find any evidence of association between delaying menopause and resulting cardiovascular disease, body mass, risk of death, Alzheimer’s disease or change in lipid levels.
The team also found that increase in alcohol consumption and tobacco smoking were associated with earlier onset of menopause. Women who drank to maximum recommended limits experienced menopause a year earlier than those who drank moderately and each additional cigarette smoked a day accelerates the onset by 2.5 weeks.
The researchers further noted that genetically altering menarche or the start of menstruation also affected the onset of menopause. For each year that menarche was advanced, menopause advanced by 8 weeks.
More findings about women’s reproductive health is expected to aid in assistive fertility and conception treatments, as well as age-related illnesses in women.
(Edited by Rachel John)
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