In a study of more than 800 Australian and UK twin pairs, lead by Dr Roger Gosden, Professor of Reproductive Biology at Weill Medical College of Cornell University in New York, premature ovarian failure was between three and five times greater when measured at age 40 and age 45 than in the general population. Ovarian failure before the age of 40 normally affects only around one woman in a hundred.
The finding applied whether or not the twins were identical (monozygotic) or non-identical (dizygotic). It confirms tentative previous data on premature ovarian failure (POF) in non-identical twins, but it is the first time it has been established in identical twins as well.
However, there were twins in the study where the menopausal ages were very different – a disparity of more than 20 years in a few cases. It was disparity in menopausal ages among twins that led to this study. First, it was prompted by the recent case of ovarian transplantation between 24-year-old identical twins at the Infertility Center in St. Louis carried out by this study’s co-author Dr Sherman Silber. One twin had undergone unexplained POF at age 14, but this was reversed through ovarian tissue transplantation from her sister, and she later conceived. Subsequently, several more identical twin pairs came forward for possible treatment and the researchers received anecdotal information about other cases of disparity in menopausal ages among twins.
“It prompted us to test the hypothesis that POF is more prevalent in identical twins than in the general population,” explained Dr Gosden.
They analysed data from 428 twin pairs on the Australian twin register and 404 on the UK twin register who had undergone a natural menopause and compared them with a control group of an ethnically comparable population of 3,483 Dutch women recruited for a breast screening programme, most of whom were post-menopausal with a mean menopausal age of just over 50.
“Our study validates the hypothesis that twins have a statistically significantly higher prevalence of POF than women generally. The differences were large at three to five-fold at both the 40- and 45-year threshold and were similar in both the national registers. The reason that the association between twins and POF has been largely overlooked up to now is probably because POF is still uncommon, even in twins, (3 to 5 in a hundred),” said Dr Gosden.
He said the surprising finding was that POF was just as common in non-identical twins as in identical twins.
“It may be that, contrary to the usual situation of non-identical twins being more common in women past the prime age of fertility (20s), in mothers whose biological clock is running faster than normal and whose ovarian reserve is running low, the likelihood of having twins shifts to an earlier age – to their peak childbearing years. So, even though they are non-identical, one or both twins born to these mothers may be inheriting her tendency to early menopause.”
With identical twins, the explanation for the excess of POF would be different according to Dr Gosden, and was, as yet, unknown and more puzzling. Studies in twins and mother-daughter pairs had shown a strong heritable component for menopausal age, although the genetic factors responsible were still largely unidentified. The current study was consistent with this finding insofar as identical twins had lesser disparities in menopausal age than non-identical twins. In several diseases such as familial breast cancer or Alzheimer’s disease, forms linked with mutations in single genes occur earlier in life than do sporadic cases. So, perhaps, it would not be surprising if identical twins were more synchronised for POF than for later menopause.
“We haven’t been able to make much progress towards understanding the mechanism in identical twins because of lack of suitable animal models. But, there are two possibilities that we may be able to check. First, discordant ovaries could arise if early post-implantation embryos split unequally during the critical period when progenitor germ cells are forming. Then a subnormal number of follicles might form in one twin. Second, there could be competition in the uterus and the stress might encourage abnormalities in the ways the genes needed to make eggs are expressed in the ovaries of each twin. We are not looking for mutations in the DNA sequence, but gene switches, a topic called epigenetics.”
Dr Gosden said that while the great majority of identical and non-identical twins can expect to reach menopause at a similar age to singletons there were clinical implications for a twin with POF whose sibling is still fertile.
“The first option is of ooctye donation for both identical and non-identical twins. For identical twins, in addition, we now have the possibility of ovarian tissue grafting. That might even be considered in some rare cases for non-identical twins if there is a good tissue match.“This is an important development as, although proportionately rare, the numbers of cases could be substantial in large countries. In the USA, for example, there are 150,000 identical twin pairs in the 20 to 40 age bracket. About 6,000 individuals (4%) will have POF before they are 40 and the data predict a substantial proportion of these will have a sister with a larger ovarian reserve and a likely later menopause.“
Prevalence of premature ovarian failure in monozygotic and dizygotic twins. Human Reproduction. doi:10.1093/humrep/del382.
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