Women may pass a genetic risk onto their sons, not just their daughters.
Sons of women with polycystic ovary syndrome (PCOS) have an increased risk of obesity and metabolic dysfunction, new research suggests.
While PCOS has a known genetic component (daughters of women with PCOS have five times the risk of developing the syndrome themselves), the exact association between sons of women with PCOS and weight or hormone problems is unclear.
Now, a new study in Cell Reports Medicine has found sons of women with PCOS are 51% more likely to develop obesity compared to sons of women without PCOS.
“These findings are important because they highlight the risk of passing health problems down through the male side of a family… and they may help us in the future to find ways to identify, treat and prevent reproductive and metabolic diseases at an early stage,” senior author Professor Elisabet Stener-Victorin, PCOS researcher at the Karolinska Institutet in Sweden, said in a statement.
Researchers used Swedish national databases to track lifetime obesity diagnoses among almost half a million boys. Around 10,000 of these had a mother with PCOS.
A further subgroup analyses found that the sons of overweight women with PCOS were 60% more likely to be obese, but sons of women with PCOS and a BMI of less than 25 had no heightened risk.
Researchers also undertook a case-control study of 171 Chilean boys aged 8-18 years, and found that those born to mothers with PCOS had higher circulating cholesterol and low-density lipoprotein cholesterol compared with sons of mothers without the condition, even at Tanner II-III and Tanner IV-V levels of maturity.
They also had multiple elevated microRNAs that regulate genes known to increase the risk of developing PCOS, suggesting these children may carry a genetic factor that increases the likelihood of developing a PCOS-esque phenotype.
“These findings demonstrate that sons of obese women are more metabolically affected and highlight the importance of weight counselling and preferably weight reduction prior to pregnancy, especially in women with PCOS,” the authors wrote.
The findings from the two human cohorts were deepened by a subsequent animal study, in which researchers teased apart the role of mothers’ androgen levels or a fat- and sugar-rich diet on male offspring.
Researchers studied the lineages of four groups of mice: one group given a high-fat, high-sucrose diet (the obese group), one group given dihydrotestosterone (to mimic the hormonal imbalance of PCOS), one group given both the high-fat, high-sucrose diet and dihydrotestosterone (combination), and one group that was given a normal diet and kept free from excess androgen exposure (control group).
Male mice whose mother belonged to the obese, PCOS or combination groups had increased fat mass, altered energy metabolism and several reproductive dysfunctions (including decreased testis size) compared to male offspring born to mothers in the control group.
These findings provide further evidence of the adverse maternal-fetal environment associated with PCOS, and obesity affects male offspring, the authors said.
“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,” study author Associate Professor Qiaolin Deng, also from the Karolinska Institutet, said in a statement.
The authors pointed to a recent study that found men with high polygenic risk scores for PCOS were at increased risk of obesity, type 2 diabetes, cardiovascular disease and male-pattern baldness, suggesting sons born to mothers with PCOS could face similar risks
Awareness of the genetic risk for male relatives of women with PCOS – fathers, brothers and sons – is growing, according to a leading expert.
“The upcoming 2023 International Guidelines in PCOS recognise the increased risk for relatives and recommends increasing awareness and education around these risks,” Professor Helena Teede, an endocrinologist and professor of women’s health at Monash University, told The Medical Republic.
The updated version of the international evidence-based guidelines for the assessment and management of PCOS will be released in July 2023.