A woman with a family history of early menopause is herself likely to have an early menopause and consequently early reproductive failure, concludes the team of Dutch researchers who have carried out the world's first study in non-twin sisters of the genetic factors involved in natural menopause.

The age of menopause is a retrospective marker for a woman's reproductive capacity in the years beforehand. The research team believes that finding that heritability plays such a major role in determining the menopause has important implications for women when childbirth is being delayed well beyond the age of 30.

It was this social phenomenon that prompted them to undertake the project.

The teams, from centers in Utrecht and Wageningen, collected data from 243 non-twin sisters in 118 families among a random population sample participating in a breast cancer screening project that had begun in the 1970s. They also collected data from 22 non-identical and 37 identical twins.

In the breast cancer screening study, all the women had agreed to provide extensive information about their health, their families and reproductive history for compilation on a database designed for research purposes.

Using three different analytical models, the researchers established nearly identical results: for non-twin sisters, the age at which they reached menopause was 85-87% down to genetic factors. In twins, it was 70-71% -- a figure which was not statistically significantly different from that of the non-twin sisters.

Research leader Dr Jan-Peter de Bruin from the Department of Obstetrics and Gynaecology at the University Medical Centre in Utrecht said that they had undertaken the project because they saw a serious social problem emerging with women delaying the age at which they have their first child.

"The increasing age at which women become pregnant with their first child is one of the most remarkable demographic changes in the last 30 to 40 years. More and more women will face involuntary childlessness if this trend keeps going," he said. "A woman with one or more first degree relatives with a history of early menopause is liable to experience earlier menopause herself. Further, this same woman is also expected to start becoming less fertile and to be completely infertile at an earlier age, thus being at greatly increased risk of remaining childless if she delays childbearing."

Previous research from the team showed that menopause was preceded by the onset of sub-fertility, infertility and irregularity of periods at distinct mean time intervals of 20, 10 and 6 years respectively.

A woman's store of eggs declines throughout her life. When stores are exhausted, this triggers the menopause.

"Probably the onset of decreasing fertility and the end of fertility is also triggered by earlier thresholds in the number of eggs, so the genetic factors that determine the age of menopause are likely to be the same factors that determine the rate at which the eggs decrease.

"This means that the woman destined to have an early menopause is also likely to be destined to become sub-fertile at an early age," said Dr. de Bruin.

"If our hypothesis is correct, then it would be sensible for a woman to make herself aware of the age at which her female relatives have reached menopause: if she wants a family it could help her decide whether it is wise to postpone motherhood too long," he added.

However, he warned, this does not mean that it is wise for a woman to assume that if her female relatives had a late menopause she can safely postpone motherhood. Menopausal ages between relatives still vary greatly.

Women with normal reproductive aging still face a rapid decline after their mid-thirties in the chance of becoming pregnant and an increasing risk of miscarriage and chromosomally abnormal babies.

Dr. de Bruin's team is collaborating with the Department of Human Genetics at the University Medical Centre to identify candidate genes for controlling the menopause. In the two years since the study started, they have obtained genetic material from 100 sister pairs who had undergone early menopause and 100 sister pairs who had undergone late menopause.

"We expect to have results about five years from now. If we do succeed in isolating the responsible genes it is a distinct possibility that young women in the future will be able to have a DNA test that will predict their age of menopause.

"Women invest a lot of years in education and work to obtain a professional career. It would be an advance if we can, at least, discriminate from this group those who are really at risk of early reproductive failure," de Bruin said.

He did not foresee gene therapy being able to correct the factors that lead to early menopause because it was likely that a large number of different genes were involved.

"But if we know the responsible genes and for which protein they code, we might start to understand what triggers resting follicles to leave the ovarian store and we may then be able to develop treatments to slow down this process," he said.

(Reference: The role of genetic factors in age at natural menopause. Human Reproduction. Vol 16. No 9. pp 2014-2018)

30-Aug-2001