The results of a study by researchers at Karolinska Institutet indicate that sons of women with polycystic ovary syndrome (PCOS) are three times more likely to develop obesity. The team made their observations through an evaluation of both human registry data, and the results of a prior clinical case control study. The researchers then confirmed their findings experimentally, in the male offspring of mothers who were diet-induced obese and/or exposed to dihydrotestosterone during pregnancy.

“Through these experiments, we can show that obesity and high levels of male hormones in the woman during pregnancy can cause long-term health problems in the male offspring. Their fat tissue function, metabolism, and reproductive function deteriorate, which in turn affects future generations,” said Qiaolin Deng, PhD, associate professor at the department of physiology and pharmacology, Karolinska Institutet.

The team said the study findings highlight a previously unknown risk of passing PCOS-related health problems across generations through the male side of a family. Reporting on their study in Cell Reports Medicine (“Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome“) Deng and colleagues noted, “Our study now provides evidence that PCOS-sons have altered lipid profiles and are at higher risk to childhood obesity.”

PCOS is caused by the ovaries producing too much of the sex hormone testosterone—hyperandrogenism. The disease affects around 15% of women of childbearing age worldwide and is a condition that can make it difficult to get pregnant. In addition, the disease is associated with various health problems, which may include diabetes or mental illness. More than 50% of women with PCOS are obese.

Daughters of women with PCOS have a fivefold risk of developing the same disease, and while it is not yet clear how sons of women with PCOS (PCOS-sons) are affected, research suggests that they are more likely to have weight and hormone problems. “Although a distinct phenotype of male offspring related to PCOS has not yet been defined, sons born to mothers with PCOS display increased body mass index (BMI), insulin resistance, and prepubertal signs of reproductive dysfunction, with increased antimüllerian (AMH) hormone levels, indicating increased Sertoli cell number,” the investigators wrote.

For their reported study, the researchers used both registry data and mouse models to determine if and how PCOS-like traits are passed from mothers to their sons. Their previous findings indicated that PCOS-sons have increased BMI and abnormal glucose and lipid metabolism. “Besides, they have increased AMH levels during infancy, childhood, and adulthood as well as smaller testicular volume,” the team noted.

To follow up these findings in a large cohort, the researchers carried out a Swedish nationwide register-based cohort study to investigate whether PCOS-sons are more often diagnosed with obesity. Just over 460,000 sons born in Sweden between July 2006 and December 2015 were included in the registry study. Of these, roughly 9,000 were sons of women with PCOS. The researchers then identified which of the children were obese. The team also used data from a longitudinal case-control study from Chile.

“We discovered that sons of women with PCOS have a threefold risk of obesity and of having high levels of “bad” cholesterol, which increases the risk of developing insulin resistance and type 2 diabetes later in life,” said study lead Elisabet Stener-Victorin, PhD, professor at the department of physiology and pharmacology, Karolinska Institutet.

These findings were confirmed in the experimental mouse study. For this work, female mice were fed—before and during pregnancy—either a standard diet or a diet rich in fat and sugar, with some of the mothers also exposed during pregnancy to high levels of the male sex hormone dihydrotestosterone. These four groups of females mimicked the pregnancies of normal weight individuals, obese women, normal weight women with PCOS, and obese women with PCOS.

The male offspring of these mothers were then fed a standard diet until adulthood, when their fat distribution and metabolism were examined. The male offspring of the PCOS-model mothers did put on more weight. “F1 male offspring in the androgenized and in the androgenized and obese lineages, respectively, gained more weight,” the authors stated. “We could see that these male mice had more fat tissue, larger fat cells, and a disordered basal metabolism, despite eating a healthy diet,” noted Stener-Victorin.

To investigate the reproductive function of the offspring and whether physiological characteristics can be passed on from generation to generation, the first-generation (F1) male mice were mated with healthy female mice that were not exposed to male sex hormones or a diet rich in fat and sugar. The whole process was repeated in the second generation (F2) to reach the third generation (F3), which was the first generation found not to be affected by maternal PCOS. “Both F1 and F3 male offspring in the androgenized and in the obese lineages, respectively, had more fat mass.” The results, the researchers noted, “suggest that metabolic dysfunction in F1 male offspring as an effect of maternal obesity or prenatal androgen exposure are transmitted across generations, whereas the trans-generational effect in the combined obese and androgenized lineage is less pronounced … Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in F1 male offspring are passed down to F3.”

They also found changes in the expression of small noncoding RNAs in the sperm of male offspring, down three generations. These results, they stated, “showed that prenatal androgen exposure and/or maternal obesity resulted in the transmission of reproductive and metabolic traits to F3 male offspring associated with common DEsncRNAs in sperm of F1, F2, and F3 offspring (i.e., transgenerational DEsncRNAs) … Moreover, we found that several DEsncRNAs in serum from PCOS-sons are shared with transgenerational DEsncRNAs in mouse sperm, highlighting the translational relevance of our transgenerational mouse studies.”

Together with the team’s recent findings that daughters of women with PCOS are five times more likely to be diagnosed with PCOS, and also that prenatal androgen-exposed first-generation male offspring develop an aberrant reproductive and metabolic phenotype, the overall results, they suggested, “strengthen the hypothesis that maternal PCOS could induce fetal programming, predisposing not only daughters but also their sons to adult disease due to adverse maternal-fetal environment.”

“These findings are important because they highlight the risk of passing health problems down through the male side of a family, highlight the risk of passing this kind of health problem, and they may help us in the future to find ways to identify, treat, and prevent reproductive and metabolic diseases at an early stage,” Stener-Victorin stated.

“Taken together, our comprehensive analyses have defined long-term adverse effects of obesity and prenatal androgen excess during pregnancy leading to transgenerational transmission of metabolic and reproductive traits in male progeny,” the authors concluded. “Importantly, several molecular signatures are detectible in serum from PCOS-sons, supporting the possibility of epigenetic inheritance in humans. These findings strengthen the translational significance identified in mouse models and shed light on a previously underappreciated risk of reproductive and metabolic alterations across generations via the male germline.”

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