Gene therapy with feline anti-Müllerian hormone analogs disrupts folliculogenesis and induces pregnancy loss in female domestic cats

Abstract

Abstract For female domestic cats, ovariohysterectomy is the only method of inducing permanent infertility. However, hundreds-of-millions of free-roaming cats globally highlight the necessity for alternative contraceptive approaches. One strategy involves a single injection of vector delivering a fertility-inhibiting protein for lifetime contraception. Recent studies in mice and cats have identified anti-Müllerian hormone as an excellent candidate for this type of contraception. Here, we leverage our recent characterization of the molecular mechanisms underlying human anti-Müllerian hormone synthesis and activity, to generate potent feline anti-Müllerian hormone analogs. Single intramuscular delivery of these analogs to female cats using an adeno-associated viral vector leads to a greater than 1000-fold increase in feline anti-Müllerian hormone levels, which are sustained for 9 months. High serum anti-Müllerian hormone is associated with abnormal estrus cyclicity, non-follicular ovarian cyst formation, and a progressive decline in antral follicle numbers, however, the few surviving large follicles continue to ovulate. Unlike previous studies, supraphysiologic levels of anti-Müllerian hormone do not block conception, although they are incompatible with the maintenance of pregnancy. Our findings highlight the complexity of the effects of anti-Müllerian hormone on ovarian physiology but confirm that this growth factor is a candidate for fertility control in free-roaming cats.