Researchers closer to understanding the cause of polycystic ovary syndrome

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New research shows that the most common cause of female infertility, polycystic ovary syndrome (PCOS), may be the result of a hormonal imbalance before birth. The findings have since led to a cure in mice, and a drug trial is set to begin in women later this year.

Despite being a common disorder, the underlying cause has been poorly understood. Polycystic ovary syndrome is estimated to affect between 8% and 20% of women worldwide, three-quarters of whom struggle to fall pregnant. The condition is typically characterised by high levels of testosterone, ovarian cysts, irregular menstrual cycles, and problems regulating sugar, but the causes have long been a mystery.

Treatments are available for helping affected women get pregnant, but their success rates are typically less than 30 per cent across five menstrual cycles.

Now, researchers at the French National Institute of Health and Medical Research have found that the syndrome may be triggered before birth by excess exposure in the womb to a hormone called anti-Müllerian hormone (AMH). AMH is produced by the ovaries when they release an egg as part of the menstrual cycle.

The research, published in Nature Medicine, “Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood” (able to be requested from your HHS library) found that pregnant women with polycystic ovary syndrome have 30% higher levels of anti-Müllerian hormone than normal. 

The researchers measured levels of AMH in 63 healthy pregnant women and 66 pregnant women with PCOS. All the women were 16 to 19 weeks pregnant. AMH levels are normally low during pregnancy as the ovaries aren't stimulated to release eggs. Since the syndrome is known to run in families, they wondered if this hormonal imbalance in pregnancy might induce the same condition in their daughters.

To test this idea, they injected excess anti-Müllerian hormone into pregnant mice. As their female offspring grew up, they displayed many of the hallmarks of polycystic ovary syndrome, including later puberty, infrequent ovulation, delays in falling pregnant, and fewer offspring. The excess hormone seemed to trigger this effect by overstimulating a set of brain cells that raise the level of testosterone.

The team were able to reverse this effect in the mice using cetrorelix, an IVF drug routinely used to control women’s hormones. Cetrorelix works by blocking another hormone, gonadotrophin. Gonadotrophin levels are known to be raised in women with PCOS. After treatment with this drug, the mice stopped showing symptoms of polycystic ovary syndrome.

The researchers wrote that “these findings highlight a critical role for excess prenatal [anti-Mullerian hormone] exposure and subsequent aberrant Gonadotropin-releasing hormone (GnRH) receptor signalling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.”

The team is now planning a clinical trial of cetrorelix in women with the condition, which they hope to start before the end of the year.

“It could be an attractive strategy to restore ovulation and eventually increase the pregnancy rate in these women,” said lead researcher Paolo Giacobini.

Robert Norman, Professor of Reproductive & Periconceptual Medicine at the University of Adelaide, who was not involved in the study, told New Scientist magazine that if the syndrome is indeed passed from mothers to daughters via hormones in the womb, that could explain why it’s been so hard to pinpoint any genetic cause of the disorder. “It’s a radical new way of thinking about polycystic ovary syndrome and opens up a whole range of opportunities for further investigation. It’s something we’ve been stuck on for a long time,” he said. 

The findings may also explain why women with the syndrome seem to get pregnant more easily in their late 30s and early 40s. Anti-Müllerian hormone levels are known to decline with age, usually signalling reduced fertility. But in women who start out with high levels, age-related declines may bring them into the normal fertility range, although this still needs to be tested, Norman said.

The results of this research are still open to interpretation and do not yet provide fertility hope for women with PCOS. The syndrome has been quite the enigma for the world of gynaecology, but hopefully this human trial can shed some light.