POlycystic ovary syndrome – a hormonal disorder that can manifest as irregular menstrual cycles, increased testosterone levels, or enlarged ovaries with many cysts – is a major cause of infertility in women, affecting up to a person in five of childbearing age. Yet the underlying mechanisms and causes of PCOS remain poorly understood.
PCOS is often familial. Up to 70% of daughters of women with PCOS also develop it, but genetic variation does not fully explain the high incidence within families. This has led scientists to suspect that other factors, such as epigenetic mechanisms, may play a role in the transmission of the disease to future generations.
A study published this week (February 3) in Cell metabolism suggests that mice can transmit PCOS-like symptoms for at least three generations. This is probably transmitted in the form of epigenetic changes, which, like a set of instructions dictating which genes are to be expressed, are inherited from parents to offspring. The researchers also analyzed the blood of women with PCOS, reporting that the samples exhibited epigenetic alterations similar to those seen in mouse models.
After two or three weeks of treatment, this epigenetic drug was able to both restore ovulation in these animals and significantly improve their metabolic alterations. I did not expect such a quick recovery.
âPaolo Giacobini, National Institute of Health and Medical Research
For Margrit Urbanek, a polycystic ovary syndrome geneticist at Northwestern University, “the article demonstrates a clear transgenerational epigenetic inheritance of PCOS-like traits in mice,” she writes at The scientist in an email. “This suggests that this could also be the case in humans but does not prove it,” adds Urbanek, who was not involved in the study.
In previous research, developmental neuroscientist Paolo Giacobini of the French National Institute of Health and Medical Research and his colleagues had identified a potential cause of PCOS. Injecting excess anti-MÃ¼llerian hormone (AMH) into pregnant mice would result in the development of PCOS symptoms in their young, including increased testosterone, irregular breeding cycles and smaller litters. They also found that AMH levels were elevated in pregnant women with PCOS compared to healthy pregnant women. Obviously, âwe have a condition that develops in the mother’s womb and is most likely transmitted to the fetus as a result of. . . it’s abnormal in utero [environment], says Giacobini.
In the new research, he and his colleagues investigated whether mice could pass these PCOS-like symptoms down through generations. To do this, they mated male and female animals whose mothers had been exposed to AMH in the womb, then mated their female offspring with males exposed to AMH in utero, creating a third generation of mice. . For this last generation, the most recent fetal exposure to AMH involved their father and maternal grandparents. To Giacobini’s surprise, when examining about fifteen third-generation females, “we saw all the reproductive defects typical of PCOS,” he recalls. They had ovulatory dysfunction, smaller litters than usual, as well as some metabolic symptoms that occur in people with PCOS, such as weight gain and features of type 2 diabetes. The team observed similar ovulation and fertility defects when she repeated the breeding protocol with healthy males from lines that had never been exposed to excess AMH, “suggesting that these defects were inherited from. .. women, âsays Giacobini.
PCOS methylation profiles
Suspecting that symptoms might be transmitted through epigenetic mechanisms, the team closely examined the genomes of third-generation females using techniques to study methylation patterns of genomes. Methylated genes are generally repressed. The researchers revealed a scattering of genes with unusual methylation patterns, often with surprisingly low methylation levels compared to methylation profiles in control mice. The most affected gene pathways were involved in the regulation of reproductive and metabolic functions, including insulin signaling and inflammation, explains Giacobini. (He and several of his colleagues have revealed that they have filed a patent application for methods of diagnosing and treating PCOS.)
In particular, genes deprived of methylation included Tet1, which encodes the ten-eleven translocation methylcytosine dioxygenase, an enzyme essential for the elimination of methylation.
They also performed DNA analyzes on blood samples from more than 30 women with PCOS, some of whom were the daughters of mothers with PCOS. Interestingly, they found that Tet1 was one of several genes that exhibited the same private methylation signature that they observed in mice.
“We really think that [Tet1] is one of the key genes whose alteration could be responsible for. . . hypomethylation that we see in both PCOS mice and women with PCOS, âsays Giacobini. The team hypothesizes that an initial burst of AMH in the uterus – directly or indirectly through effects on other hormones – somehow reprograms the methylation state of key genes such as Tet1, thereby influencing the expression of other genes, resulting in symptoms of PCOS.
He supports the idea that AMH has a direct role in the pathogenesis of PCOS rather than being a consequence of PCOS.
âMargrit Urbanek, Northwestern University
Further reinforcing this hypothesis, the team found that they could reverse some of the symptoms in third-generation females by injecting them with a natural methylation-promoting molecule called S-adenosylmethionine. Remarkably, “after two or three weeks of treatment, this epigenetic drug was able to restore both ovulation in these animals and considerably improve their metabolic alterations”, explains Giacobini. “I didn’t expect such a quick recovery.”
For Elisabet Stener-Victorin, researcher in reproductive physiology at the Karolinska Institute, this last result is particularly intriguing. Noting that the agent used in the study is a relatively nonspecific epigenetic modifier that affects all cells, it may be useful to explore the effect and mechanisms of more targeted agents in future studies in the possible goal of finding treatments for PCOS.
Perhaps the most intriguing finding “is that they can translate this and see at least some of these epigenetic changes in the serum of women with PCOS,” she says, adding that some of her previous research has also revealed epigenetic changes in patients with PCOS. Such findings could pave the way for the development of potential biomarkers to predict PCOS, adds Stener-Victorin, who has collaborated with Giacobini in the past but was not involved in the new research.
The role of AMH in PCOS
Urbanek writes that she finds the close resemblance between the AMH-induced mouse model and human patients striking, as well as the fact that the epigenetic effects have been maintained so strongly for three generations. “This supports the idea that AMH has a direct role in the pathogenesis of PCOS rather than being a consequence of PCOS,” she writes. âIt also raises a warning flag about the significant impact that exposure to hormones can have on a multigenerational timescale. For humans, this means that a woman’s exposure to hormones would always impact her. grandchildren and great grandchildren 50 years or more later.
Urbanek and Stener-Victorin say they are curious to learn more about the underlying mechanisms – for example, how exactly AMH causes these epigenetic changes to begin with, and whether it is directly caused by AMH or indirectly by elevation. resultant testosterone, which was elevated in second and third generation offspring mice, notes Stener-Victorin.
Another conundrum is how this epigenetic pattern is maintained across generations: is it transmitted directly via germ cells, or do high concentrations of hormones somehow generate the epigenetic changes to each generation? To answer this question, it would be helpful to see epigenetic analyzes of germ cells in particular, rather than whole ovaries, as well as data on AMH concentrations in the second and third generation, the two researchers note. It is “important to separate what is entrained by the germ cells and what is an effect in utero,” says Stener-Victorin. Another limitation of the research, she adds, is that the team is comparing methylation patterns in second and third generation rodents with those in first generation control mice; ideally, each generation is compared to an equivalent generational witness.
One open question that Giacobini hopes to answer is whether such epigenetic effects could influence male offspring as well. Her study focused on female mice because by definition PCOS affects women. But if PCOS is mediated by changes in the expression of influential epigenetic actors such as Tet1, then it could affect all the offspring, as some of the preliminary data from his lab already suggests, he says. So far, because clinicians rarely monitor the health of boys born to women with PCOS, let alone monitor them over time, “we don’t really know in humans whether the sons of women with PCOS could [also] have long-term health consequences.
N. El Houda Mimouni et al., “Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process”, Metab cell, doi: 10.1016 / j.cmet.2021.01.004.