How is PCOS (Polycistic Ovary Syndrome) passed down from mother to daughter?

For the first paper, I chose a recent article out of Nature Medicine by Risal et al.  at the Karolinska Institutet in Stockholm, Sweden.  I chose this paper because PCOS, can be awful for the women suffering from it. In addition to the medical symptoms, they may also deal with the societal stigma of obesity, a frequent symptom of PCOS.  Because PCOS is a hormonal and metabolic disorder, women with PCOS often have a harder time losing this extra weight, which is not apparent to others who only observe a larger body, and unfortunately often judge.

Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Risal S, Pei Y, Lu H, Manti M, Fornes R, Pui HP, Zhao Z, Massart, Ohlsson, Lindgren, Crisosto N, Maliqueo, Echiburú , Ladrón de Guevara A, Sir-Petermann T, Larsson H, Rosenqvist MA, Cesta CE, Benrick A, Deng Q, Stener-Victorin .Nat Med. 2019 Dec;25(12):1894-1904. doi: 10.1038/s41591-019-0666-1. Epub 2019 Dec 2.

PCOS, or Polycystic Ovarian Syndrome, is a common hormonal disorder which affects women of reproductive age.  Women with PCOS don't always have cysts on their ovaries , but do have a host of other symptoms including:  irregular periods, excess facial hair, obesity, and a higher risk for diabetes and high blood pressure.  These symptoms arise from greater production of male hormones.  While PCOS does appear to be passed down from mother to daughter,  a single clear genetic marker for has not been identified.  

This article uses data collected from patients, as well as a mouse model to directly test the effect of elevated male hormones during pregnancy.  In this way they tie clinical observations with a system that they can test and prove whether their theories are true.  It is interesting enough to show certain biological factors correlate with a condition, but to actually be able to manipulate those factors and show that the disorder is changed, is one of the huge benefits of animal models in biomedical research.  

Using data collected from women in Sweden and Chile, the authors discovered that daughters were more likely to have PCOS, and the associated symptoms, if born to mothers with PCOS.  Though it was not a perfect correlation.  Women with PCOS still had daughters not affected, and women without PCOS had daughters with the condition.  However, the greater likelihood of mother-daughter pairs with PCOS, lead the researchers to test this question further. 

Using their mouse model, the researchers studied both the effects of elevated male hormones and obesity during pregnancy.  For simplicity, I'll only discuss the results of hormonal treatments.  The mice that received extra male hormones during pregnancy had less successful pregnancies, with smaller litter sizes and more miscarriages.  Interestingly, the PCOS-like symptoms in the daughter mice were present, even if they did not have elevated male hormones themselves.  This indicates that exposure to these hormones, while they are still developing in their mother, was the strongest determinant if they would develop symptoms in adulthood.  One of the advantages of being able to test in a mouse model, is the accelerated time to study the next generation of daughters, which would take decades of observations in human families.  Later generations of mice that had elevated male hormones during the first generation pregnancy also displayed some of these symptoms, though not as pronounced as in the first generation daughters.

This suggests that the effects of high levels of male hormone during pregnancy have a longer lasting effect on daughters and their future offspring.  Recall, these daughters did not necessarily have elevated male hormones themselves.  This lead the researchers to see if the first generation daughter's egg cells, which would pass genetic information on to their own daughters, were affected by hormonal conditions in the womb.

The researchers employed a genetic screening technique that allowed them to observe differences in over 7,000 genes in the daughter's egg cells.  They found that 410 genes were expressed differently in daughters that were exposed to higher levels of male hormones, compared to daughters that developed in normal hormonal conditions.  The researchers distilled this massive amount of information, and determined that groups of these genes controlled DNA repair, reproductive processes, and metabolic processes. These classes of genes make sense in the context of the symptoms of PCOS. 

Finally, the researchers connected the observations in mice to women with PCOS.  Several of the genes that were differently expressed in the mice egg cells were also disregulated in tissue and serum from women with PCOS.  This nicely ties their mouse model back to observations in patients.  

Overall these results suggest it is the hormonal conditions during pregnancy, and not a heritable genetic trait, which is the main factor as to whether a daughter will also have PCOS.  In addition to helping us understand better the how PCOS is passed from generation to generation, these results may give us greater insight into how to regulate the whether it is passed on through regulation of hormonal levels during pregnancy. 

So what do you think?  

Feedback is welcome, discussion on the paper even more so!