A blocking antibody against anti-Müllerian hormone restores ovulation and normal androgen levels in a spontaneous rat model of polycystic ovary syndrome

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BACKGROUND: Polycystic Ovary Syndrome (PCOS), the leading cause of infertility worldwide, is characterised by oligo-anovulation, hyperandrogenism, polycystic ovarian morphology and high Anti-Müllerian hormone (AMH) levels, associated with severe metabolic disturbances. However, the role of AMH in the physiopathology of this syndrome remains poorly understood and strategies to block its effects have never been investigated in animal models of PCOS. METHODS: We used Western-blotting, ELISA and gene reporter approaches to evaluate the blocking efficacy, interspecificity and mechanism of action of an antibody against human AMH, Mab22A2. Then, we investigated the ability of a rat version of Mab22A2, rMab22A2, to alleviate reproductive dysfunction in Goto-Kakizaki (GK) rats, which spontaneously exhibit all the features of women with PCOS. FINDINGS: We showed that Mab22A2 was interspecific, did not prevent AMH from binding to its receptor and was able to block the effects of AMH in gonadal cell lines. In addition, treatment of anovulatory GK rats with rMab22A2 reduced their bioavailable serum AMH levels and normalised their androgen concentrations. Finally, this treatment also induced ovulation in 84% of the rats and resulted in 66% of pregnancies. INTERPRETATION: Our results show that AMH is a major driver of reproductive and hormonal dysfunction in PCOS and provide proof of concept that a blocking antibody against AMH can reverse the major reproductive dysfunction observed in PCOS, opening up promising avenues for the treatment of patients with PCOS. FUNDING: Inserm, Sorbonne University, Inserm Transfert, the French Endocrine Society and the Medical Research Foundation (grant agreement n°EQU201903007868).

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