Polycystic ovary syndrome is common, it can be debilitating, and it's the main cause of female infertility worldwide. Yet despite years of research and speculation, nobody was sure how it even starts - but now we finally have an exciting lead.
For years, researchers assumed that the condition started in the ovaries, though recent research has found evidence to suggest it actually starts in the brain.
Now, a new study has struck a nice balance between both hypotheses, indicating that the path for polycystic ovary syndrome (PCOS) could be set before a girl is even born.
A team led by researchers from the University of Lille in France has arrived at some tantalising results suggesting PCOS is developed when a hormone produced by the ovaries interacts with a set of neurons in the mother's brain.
The interaction can initiate a cascade effect, disrupting enzymes in the placenta and ultimately causing PCOS symptoms in the offspring. Given that PCOS tends to run in families, this explanation would make a lot of sense.
Polycystic ovary syndrome is a set of symptoms related to hormone imbalance that still has no universal definition. Women with the condition can experience weight gain, large ovarian cysts, difficulty ovulating, acne, facial hair, depression, and agonising and heavy periods.
Once women are diagnosed, which can often take years, treatment options are seriously limited, usually involving hormonal medication in the hopes it might alleviate the symptoms. Even with treatment, in the long-term PCOS can lead to metabolic disorders like type 2 diabetes, cardiovascular disease and even infertility.
But results from this new study have the potential to eventually change the way we view the condition, which affects one in 10 women worldwide.
This latest research focussed on the antimüllerian hormone (AMH), which is produced by follicles located on the outside of the ovary.
Previous research has shown that AMH could interact with neurons in the brain, which then cause the pituitary gland to release luteinizing hormone (LH) - the same hormone that surges at certain times of the month to trigger ovulation.
Women with PCOS, however, have constant high levels of LH, which inhibits ovulation and boosts the release of testosterone – two telltale signs of the condition.
To explore the role of AMH further, the researchers analysed the blood samples of four groups of women in their second trimester of pregnancy. These four groups included obese and non-obese women with and without PCOS.
Surprisingly, the team found that non-obese women who have PCOS had AMH levels that were about two to three times as high as in the other groups.
The researchers then moved on to mouse models so they could easily investigate how these high hormone levels might affect female offspring. They injected pregnant mice with the antimüllerian hormone, mimicking the hormonal imbalance they'd found in the women with PCOS.
Sure enough, after this AMH treatment the next generation of female mice developed symptoms that are very similar to PCOS - such as elevated testosterone levels and disrupted ovulation.
The team thinks that all this could be happening because having too much AMH could inhibit an enzyme in the placenta called aromatase, which normally works to convert testosterone into estrogen.
If that conversion doesn't happen as efficiently, the foetus in the womb could be exposed to way more testosterone than normal, leading to hormonal changes in the future.
It's a strong hypothesis, but scientists will need to continue working to figure out if what they've observed in mice really does happen in women, too.
"Whether all these things happen in humans, we don't know," Jeffrey Chang, a reproductive endocrinologist at the University of California San Diego (UCSD), told Science.
In this case, there is a key discrepancy between mouse models and human models: human placentas contain a lot more aromatase. The dissimilarity means that it could be harder for testosterone to overwhelm enzyme activity in humans.
Nevertheless, most researchers agree that testosterone levels, which are directly affected by AMH, play a key role in the development of PCOS.
The researchers are now planning to investigate how offspring are affected when hormones like testosterone are regulated during pregnancy.
The study has been published in Nature Medicine.