Researchers from the French National Institute of Health & Medical Research (Inserm), University of Lille in Lille, France, and the university’s teaching hospital CHU de Lille have identified a promising new therapeutic strategy for polycystic ovary syndrome (PCOS). In preclinical models, the use of antibodies that block the activity of anti-Müllerian hormone (AMH) helped prevent the onset of PCOS-like symptoms — and even reversed them in adults who were already affected. Paolo Giacobini, PhD, neuroendocrinologist and group leader at Inserm’s Lille Neuroscience and Cognition Research Center (Centre de recherche Lille Neuroscience et Cognition), shared the findings with Medscape’s French edition.
Reduced Quality of Life
PCOS is one of the most common causes of infertility among women of reproductive age, affecting approximately 1 in 10 women — or more than two million individuals in France alone. Currently, treatment options are limited to symptom management.
“This condition has a significant impact on women’s quality of life,” said Giacobini. “It presents with a broad spectrum of symptoms that vary between patients, including polycystic ovaries, elevated androgen levels leading to menstrual irregularities, acne, hair loss, excessive body hair, high levels of AMH, and, in some cases, metabolic syndrome. At least half of women with PCOS have associated comorbidities such as overweight or obesity, elevated insulin levels that increase the risk of developing type 2 diabetes, or cardiovascular disease.”
A Multifactorial Condition
Diagnosis of PCOS is typically based on the presence of at least two of the following three criteria: irregular menstrual cycles, clinical or biochemical signs of hyperandrogenism, and polycystic ovarian morphology as observed via ultrasound.
The exact cause of PCOS remains unclear. “We’ve done extensive laboratory research using preclinical models to better understand the heritability of the syndrome,” Giacobini said. “Genetics are a factor, but they do not fully explain the high prevalence. We’ve also identified epigenetic changes and environmental influences, such as hormonal exposures during fetal development or after birth. It is highly likely that PCOS has a multifactorial origin.”
In a recent study, Giacobini’s team focused on the role of AMH. In PCOS, the ovaries produce excess AMH, which impairs the maturation of follicles and contributes to androgen overproduction. “In previous preclinical studies, we found that prenatal exposure to AMH could induce PCOS-like symptoms in offspring, and these symptoms were transmitted across generations,” Giacobini explained. “We then examined critical periods of vulnerability in humans and observed that children of women with PCOS — both daughters and sons — had elevated AMH levels, even before puberty. We also found that mice exhibited high AMH levels during ‘mini-puberty,’ a transient hormonal phase in early infancy.”
Blocking AMH Receptors
The research team next investigated whether blocking AMH could help prevent PCOS. To do this, they developed a novel antibody, Ha13, designed to block AMH receptors located both in the ovaries and on gonadotropin-releasing hormone (GnRH)-producing neurons, which regulate reproductive function.
“By administering this antibody to young mice during the mini-puberty phase, we were able to prevent the development of PCOS in adulthood,” said Giacobini. “And when we treated adult mice already exhibiting PCOS symptoms, we reversed all reproductive abnormalities — normalizing menstrual cycles, ovulation, and androgen levels.”
Giacobini views this study as “a gateway to further research on the pharmacokinetics of this antibody, which could eventually pave the way for human trials.” Although the molecule has been patented, several steps remain before it can be considered for clinical use. “The effects in animals are very promising, but we still need to evaluate long-term outcomes and establish optimal dosing,” he emphasized.
An Advanced Alternative
Another therapeutic avenue targeting the GnRH receptor is already further along in development. “We published our preclinical research on GnRH antagonists in 2018, and, thanks to European funding, we were able to initiate clinical trials. The pilot-phase results have been encouraging,” Giacobini said.
“One advantage is that this molecule is already approved by the US Food and Drug Administration and the European Medicines Agency for other indications. We’re already familiar with its pharmacological profile and side effects, which significantly accelerates development,” he concluded.
This story was translated from Medscape’s French edition.