Periodic Reporting for period 4 - REPRODAMH (Extra-gonadal roles of Anti-Müllerian Hormone in the aetiology of polycystic ovary syndrome: the domino effect to reproductive neuroendocrine dysfunctions)
Okres sprawozdawczy: 2021-11-01 do 2023-02-28
Polycystic ovary syndrome (PCOS) is the most frequent reproductive disorder affecting 10-18 % of women worldwide (Broekmans and Fauser 2006). The condition represents the most common cause of anovulatory infertility in women (Walters et al. 2018; Escobar-Morreale 2018). It is well known that PCOS has other long-term health repercussions, including obesity, metabolic syndrome and type-2 diabetes (Stener-Victorin and Deng 2021). Collectively, these alterations have a discernible impact on the quality of life and define an enormous clinical, psychological, societal and economic burden. There is thus an urgent need to design effective therapeutic strategies aimed at curing and/or alleviating the reproductive and metabolic health-related burden of women with PCOS.
In patients with PCOS, ovarian levels of Anti-Müllerian Hormone (AMH) are elevated, indicating the potential relevance of AMH for PCOS diagnosis and management (Cook et al. 2002; Pigny et al. 2006).
Another key neuroendocrine aberration in women with PCOS is increased luteinizing hormone (LH) pulse frequency (Morales et al. 1996; Taylor et al. 1997; Ehrmann 2005; Goodarzi et al. 2011), which suggests an increase in activity of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus (Ehrmann 2005; Goodarzi et al. 2011; Dumesic et al. 2015). However, for many years PCOS has been considered mainly as a gonadal pathology and possible regulations from the central nervous system or interactions with it remained elusive.
The overall objectives of this ERC project were: to determine whether AMH might contribute to the hormonal and gonadal alterations observed in PCOS, to study the hypothalamic changes that may occur in the brain of PCOS animals as well as in women affected by this syndrome and to design and test new preclinical therapeutic strategies to treat PCOS.
In patients with PCOS, ovarian levels of Anti-Müllerian Hormone (AMH) are elevated, indicating the potential relevance of AMH for PCOS diagnosis and management (Cook et al. 2002; Pigny et al. 2006).
Another key neuroendocrine aberration in women with PCOS is increased luteinizing hormone (LH) pulse frequency (Morales et al. 1996; Taylor et al. 1997; Ehrmann 2005; Goodarzi et al. 2011), which suggests an increase in activity of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus (Ehrmann 2005; Goodarzi et al. 2011; Dumesic et al. 2015). However, for many years PCOS has been considered mainly as a gonadal pathology and possible regulations from the central nervous system or interactions with it remained elusive.
The overall objectives of this ERC project were: to determine whether AMH might contribute to the hormonal and gonadal alterations observed in PCOS, to study the hypothalamic changes that may occur in the brain of PCOS animals as well as in women affected by this syndrome and to design and test new preclinical therapeutic strategies to treat PCOS.
In patients with PCOS, Anti-Mullerian Hormone (AMH) plasma levels are elevated, indicating the potential relevance of AMH for PCOS diagnosis and management. Nevertheless, it is worth noting that until our investigations (Cimino et al. 2016; Tata et al. 2018) (Figure 1), the possible extra-ovarian effects of AMH on the hypothalamic system have not been suspected nor investigated. In a study (Tata et al. 2018) that we published in Nature Medicine in 2018, we highlighted a novel role for AMH as a fetal programming factor that contributes to the acquisition of the neuroendocrine disturbances observed in PCOS. We first showed that that pregnant women with PCOS have significantly higher circulating AMH levels, during the second trimester of gestation (Tata et al. 2018), as compared with pregnant women with normal fertility. More recently, we have further corroborated these findings showing that the serum AMH and androgens are significantly higher in women with PCOS than controls throughout pregnancy (Peigné et al. Human Reproduction, 2023). Based primarily on findings in mice, this work suggests that interactions between AMH and GnRH neurons can have a cascade effect, ultimately causing PCOS-like symptoms in the offspring. We injected some pregnant rodents with AMH late in pregnancy to mimic the high levels of the hormone in the women we have studied. The female offspring developed symptoms resembling PCOS, such as rare ovulation and high testosterone levels (Tata et al. 2018) (Figure 2). Another important aspect emerging from that study is the finding that intermittent delivery of a GnRH antagonist to adult PCOS-like animals, corrected their neuroendocrine and reproductive alterations.
More recently, we used the PCOS animal model, that we previously generated and characterized (Tata et al. 2018), to show that the transmission of reproductive and metabolic PCOS-like traits occurs across multiple generations (Mimouni et al. 2021). In this work, published in Cell Metabolism, we provided compelling evidence that the transmission of PCOS reproductive and metabolic dysfunctions to multiple generations occurs via altered landscapes of DNA methylation. Moreover, we identified methylome markers in women with PCOS as possible diagnostic landmarks and candidates for epigenetic-based therapies (Figure 3).
Women with PCOS frequently experience decreased sexual arousal, desire, and sexual satisfaction. In a study, published in PNAS in 2022 (Silva et al. 2022), we discovered that PCOS-like mice also display impaired sexual behavior and sexual partner preference over reproductive age and we unveiled a brain pathway potentially underpinning the etiology of low sexual drive in PCOS, while pointing to prospective therapeutic approaches to rescue normal sexual function in these women (Figure 4).
Finally, a recent study that I have coordinated (Barbotin et al., eBioMedicine, 2023) was the first to investigate brain structure and function in PCOS patients using proton magnetic resonance spectroscopy and diffusion tensor imaging combined with fiber tractography to explore whether hypothalamic dysfunctions could lie at the root of PCOS. Our findings demonstrate that hypothalamic activity and/or axonal-glial signaling in women with PCOS is increased as compared to control women. Moreover, we have uncovered a novel central role for AMH in the regulation of GnRH secretion by the control of cytoskeletal plasticity in the hypothalamus.
Disseminations
Overall, during this 5-year ERC-CoG, we have been very successful in terms of publications with 11 original manuscripts published in highly-ranked international Journals, such as Nature Medicine, Cell Metabolism, Science, PNAS, eBioMedicine, and 6 review/commentary articles.
In these 60 months, the PI of this project has been invited-speaker at 25 Conferences and lectures in 18 European institutions.
On top of it, the PI has co-organized 7 International Meetings containing topics related to PCOS and Infertility.
The PI and the postdocs working on this ERC project have organized the first edition of the French PCOS day-PCOS challenge (September 1th 2021, Paris, France), which was replicated in 2022, consisting of several initiatives including a round table with the National PCOS associations and with women with PCOS.
During these years, nearly 50 international press releases (articles, radio, tv…) have been published worldwide related to our discoveries obtained during this ERC project.
More recently, we used the PCOS animal model, that we previously generated and characterized (Tata et al. 2018), to show that the transmission of reproductive and metabolic PCOS-like traits occurs across multiple generations (Mimouni et al. 2021). In this work, published in Cell Metabolism, we provided compelling evidence that the transmission of PCOS reproductive and metabolic dysfunctions to multiple generations occurs via altered landscapes of DNA methylation. Moreover, we identified methylome markers in women with PCOS as possible diagnostic landmarks and candidates for epigenetic-based therapies (Figure 3).
Women with PCOS frequently experience decreased sexual arousal, desire, and sexual satisfaction. In a study, published in PNAS in 2022 (Silva et al. 2022), we discovered that PCOS-like mice also display impaired sexual behavior and sexual partner preference over reproductive age and we unveiled a brain pathway potentially underpinning the etiology of low sexual drive in PCOS, while pointing to prospective therapeutic approaches to rescue normal sexual function in these women (Figure 4).
Finally, a recent study that I have coordinated (Barbotin et al., eBioMedicine, 2023) was the first to investigate brain structure and function in PCOS patients using proton magnetic resonance spectroscopy and diffusion tensor imaging combined with fiber tractography to explore whether hypothalamic dysfunctions could lie at the root of PCOS. Our findings demonstrate that hypothalamic activity and/or axonal-glial signaling in women with PCOS is increased as compared to control women. Moreover, we have uncovered a novel central role for AMH in the regulation of GnRH secretion by the control of cytoskeletal plasticity in the hypothalamus.
Disseminations
Overall, during this 5-year ERC-CoG, we have been very successful in terms of publications with 11 original manuscripts published in highly-ranked international Journals, such as Nature Medicine, Cell Metabolism, Science, PNAS, eBioMedicine, and 6 review/commentary articles.
In these 60 months, the PI of this project has been invited-speaker at 25 Conferences and lectures in 18 European institutions.
On top of it, the PI has co-organized 7 International Meetings containing topics related to PCOS and Infertility.
The PI and the postdocs working on this ERC project have organized the first edition of the French PCOS day-PCOS challenge (September 1th 2021, Paris, France), which was replicated in 2022, consisting of several initiatives including a round table with the National PCOS associations and with women with PCOS.
During these years, nearly 50 international press releases (articles, radio, tv…) have been published worldwide related to our discoveries obtained during this ERC project.
The research that we have conducted during the last years, led to several paradigm shifts in the previous concepts regarding the etiology of PCOS as we were the first to propose that AMH-dependent regulation of GnRH release could be involved in the neuroendocrine control of fertility and pathophysiology of PCOS. Moreover, we have significantly contributed to the field improving the understanding of the pathophysiological mechanisms underlying the disease and identifying new targets for early diagnosis and treatment of PCOS. Indeed, we were among the first research groups in the World to provide strong pre-clinical and clinical evidences pointing to epigenetic mechanisms as potential key players in the transmission of PCOS.
Our translation into drug discovery has a strong impact on society. From the science emerging from this 5-year period, we have already filed 2 patents (N° de publication: WO2018177746; N° de publication: WO2022096633) and deposited 1 European patent request application (N° EP22305707.6) focused on novel therapeutic or diagnostic applications for PCOS.
Our translation into drug discovery has a strong impact on society. From the science emerging from this 5-year period, we have already filed 2 patents (N° de publication: WO2018177746; N° de publication: WO2022096633) and deposited 1 European patent request application (N° EP22305707.6) focused on novel therapeutic or diagnostic applications for PCOS.