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Body and mind

Elevated maternal hormones increase daughters’ risk of polycystic ovary syndrome

Daughters of women with polycystic ovary syndrome (PCOS) have a five-fold greater risk of being diagnosed with PCOS as adults. New research shows that the reason is elevated levels of male sex hormones during pregnancy, which can make PCOS hereditary over several generations.

New research confirms that the daughters of mothers with polycystic ovary syndrome (PCOS) have a five-fold greater risk of developing PCOS as adults than the daughters of mothers without PCOS

Researchers do not yet fully understand the pathophysiology of PCOS, but in a combined human and mouse study, Swedish researchers found that the combination of PCOS, elevated male sex hormones (androgens) during pregnancy and a high-fat diet can significantly affect fetal development across several generations.

This combination made conceiving viable offspring almost impossible for mice in experiments, and this surprised the researchers.

“We have identified a novel mechanism that gives rise to several investigations of how androgens may programme immature egg cells to give the daughters of mothers with PCOS reproductive and metabolic diseases as adults,” says, Elisabet Stener-Victorin, Professor, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden who led the study together with Associate Professor Qiaolin Deng from the same department.

The new study has been published in Nature Medicine.

PCOS associated with many disorders

More than 10% of women of reproductive age have PCOS, which is characterized by elevated levels of androgens, which is reflected in acne, increased hair growth in unwanted places, irregular menstruation and difficulty in becoming pregnant.

In addition, PCOS is also associated with various mental disorders, including anxiety and depression, and an increased risk of developing type 2 diabetes, obesity and other types of metabolic and cardiovascular diseases.

Although researchers have not yet determined why PCOS develops, they know that fetal development plays a role.

“The ultimate question is to what extent PCOS is caused by hereditary and environmental factors, such as exposure to androgens during pregnancy, and separating these factors has been difficult. We know that being overweight exacerbates all signs of PCOS, but we want to be able to tell women with PCOS who are thinking about getting pregnant how they can manage the syndrome,” says Elisabet Stener-Victorin.

Study of 30,000 women shows that PCOS is heritable

The researchers first investigated the hereditary component of PCOS by using a Swedish nationwide registry-based cohort of nearly 30,000 daughters of mothers with and without PCOS.

About 2700 daughters developed PCOS, which roughly corresponds to the 10% prevalence in the population.

The researchers found that the daughters of mothers with PCOS had a five-fold risk of developing PCOS compared with the daughters of mothers without PCOS.

This result was confirmed in a study of daughters of mothers with and without PCOS in Chile who were monitored until adulthood.

The hereditary component was strong.

“We examined blood samples from the daughters with PCOS in Chile, and although they were only about 20 years old, they had higher average body mass index and blood pressure and had higher circulating androgens and more frequent irregular menstrual cycles indicating both metabolic and reproductive dysfunction. These measurements actually showed that they probably had PCOS but it had not yet been diagnosed,” explains Elisabet Stener-Victorin.

Mouse experiments suggest androgens as the cause

The researchers speculated that increased levels of androgens during pregnancy could be an important factor in the hereditary predisposition for developing PCOS.

They therefore set up an experiment in which they exposed pregnant mice to androgens during pregnancy and then fed them either a high-fat and high-sucrose (obesogenic) diet or control diet.

The researchers then carefully measured the PCOS-like phenotype of the first generation of offspring and showed, as in previous studies, that the offspring of mothers who were given androgens during pregnancy were more obese, had reproductive problems themselves, had various metabolic diseases and were anxious – all characteristic signs of PCOS.

“However, it was important for us to also examine the situation across the generations so that we could determine how androgens, with or without a high-fat and high-sucrose diet, affect the third generation of offspring that have not been exposed to androgens or an obesogenic diet during fetal development,” explains Elisabet Stener-Victorin.

Researchers concerned about the results

The researchers therefore mated some of the first-generation female offspring with unexposed males to generate second-generation offspring, which were measured, and some were used to generate the third-generation offspring.When the researchers investigated the pregnancies and offspring in the first generation, they were very surprised.

Second-generation embryonic development was totally arrested among the mice whose grandmothers had been exposed to androgens and a high-fat and high-sucrose diet during pregnancy.

Only 12 of 24 females became pregnant, and among these only one offspring survived.

“We were concerned about what we saw and thought there had been a mistake, so we repeated the experiment and obtained the same result. The combination of androgens, as seen in PCOS, and a high-fat and high-sucrose diet have very devastating effects on the placenta, affecting fetal growth for several generations,” explains Elisabet Stener-Victorin.

Epigenetic changes may cause PCOS

The researchers also investigated the effect of androgens with or without high-fat and high sucrose diet and found that the female offspring experienced reproductive and metabolic problems for several generations.

“This suggests that androgens are the driving force in the hereditary component of PCOS and that poor diet with associated obesity makes everything much worse,” says Elisabet Stener-Victorin.

In addition, the researchers examined the gene expression in eggs of the first-, second- and third-generation offspring and found that several genes were differentially expressed across generations, which may help to explain how PCOS is transmitted. Of note, several of these genes were examined in the blood of the daughters of women with and without PCOS and followed the same expression pattern as in the eggs of the offspring and might be potential biomarkers to predict the development of PCOS.

The researchers knew about these genes from such sources as the development of type 2 diabetes and obesity.

“We believe that many of these genes are involved in epigenetic changes that are manifested in PCOS and several associated conditions. Maybe in the future they can be used as biomarkers to predict the development of the syndrome and to make a diagnosis,” adds Elisabet Stener-Victorin.

The hereditary component of PCOS may be treatable

The clinical perspectives of this discovery are interesting.

Identifying these epigenetic changes among women with PCOS may help researchers in making an early diagnosis and in deciding whether or not to intervene.

According to Elisabet Stener-Victorin, whether to make an early diagnosis is the right choice or not is always difficult, but the natural next step in this research will be to determine whether the changes that have taken place can be prevented and/or reversed.

There are already various types of medicine that lower the levels of androgens that may be relevant for women with PCOS before pregnancy, reducing the exposure of the growing baby to androgens, which may reduce the risk of developing the syndrome in subsequent generations.

“Another option is to examine how exercise, for example, affects the risk of transmitting PCOS from generation to generation,” says Elisabet Stener-Victorin.

Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome” has been published in Nature Medicine. The Novo Nordisk Foundation awarded grants to Elisabet Stener-Victorin for the following projects – 2016: Maternal Androgen and Obesity: Effects on Placenta and Fetus Function, on Offspring Behavior and Metabolism and on Gut Microbiome Function; 2017: Maternal Androgen Excess with or without Maternal Obesity – Does It Program Transgenerational Mitochondrial Dysfunction?

Elisabet Stener-Victorin
Professor
Elisabet Stener-Victorin established her research group Reproductive Endocrinology and Metabolism at the Department of Physiology and Pharmacology in January 2015. She was previously with the Department of Physiology at University of Gothenburg where she held a VR granted Junior Research position, and since 2009 a Senior Research position. Her group’s research activities aim to yield new key information on the pathophysiology of polycystic ovary syndrome (PCOS), the most common female endocrine and metabolic disorder. Its etiology is not well understood, but genetic, epigenetic, and environmental factors have been implicated in its development. They also investigate the effect and mechanisms of acupuncture and/or exercise on reproductive function, hyperandrogenemia and insulin resistance as well as on key molecular pathways and epigenetic modifications in adipose and skeletal muscle tissues.