Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder affecting women in reproductive age. Women with PCOS exhibit 2-3x higher levels of circulating Anti-Müllerian Hormone (AMH) as compared to healthy women and it is unclear if the elevation of AMH is a bystander effect or is driving the condition. Moreover, PCOS has a strong heritable component, however the etiopathology of the disease and the mechanisms underlying its transmission remain to be elucidated. Therefore, it is crucial to unravel contributions of intrauterine environmental factors that might induce epigenetic changes leading to increased susceptibility to PCOS later in life. We have previously measured AMH levels in a cohort of pregnant women with PCOS and control women revealing that AMH is significantly more elevated in the former group vs the latter. Pregnant mice were treated with AMH to model our clinical findings and investigate the neuroendocrine phenotype of their female progeny across multiple generations. Using this new preclinical PCOS model showed that fetal exposure to excess AMH drives a transgenerational transmission of the major reproductive and metabolic PCOS alterations across multiple generations via altered landscapes of DNA methylation. Furthermore, these findings revealed the existence of common epigenetic signature in a cohort of mothers and their daughters suffering from PCOS as well as in PCOS-like mice, which could serve as markers for early diagnosis of the syndrome. Furthermore, the efficiency of an epigenetic-based therapy used in this preclinical model of PCOS, offers a promising therapeutic avenue to improve the management of PCOS patients. Collectively, our results challenge the concept of PCOS originating in utero and appear to consolidate the role of AMH as a trigger of the pathogenesis. This work further points to PCOS-like mouse model as an excellent preclinical tool to investigate both neuroendocrine disturbances of PCOS and how developmental programming effects are transmitted, while offering a therapeutic avenue for the treatment of the disease.
Key words: PCOS, Fetal programming, AMH, GnRH, Transgenerational Transmission
21 May 2022 - 24 May 2022