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Abstract

Gain-of-function mutations in the human follicle-stimulating hormone receptor (FSHR) cause spontaneous ovarian hyperstimulation syndrome (OHSS), a serious reproductive disorder. However, the molecular physiology and treatment options for OHSS remain elusive. Notably, estrildid finches naturally carry an FSHR variant (Thr449Ala) analogous to the pathogenic mutation in humans yet are resistant to OHSS. Here we show that this resistance stems from significantly reduced luteinizing hormone receptor expression in estrildid ovarian granulosa cells. Furthermore, treatment with the luteinizing hormone receptor antagonist alleviates OHSS symptoms in mouse models. Single-cell RNA transcriptomic reveals functional compensation of the two receptors to regulate estrogen production and vascular permeability, resembling the adaptive mechanisms observed in estrildid finches. Our study unravels the molecular mechanism underlying the physiological adaptation of estrildid ovaries to high FSHR constitutive activity and is a example of how the concept of Darwinian Medicine could be exploited to identify novel drug targets for ovarian hyperstimulation syndrome treatment. Mutations in the follicle-stimulating hormone receptor (FSHR) cause spontaneous ovarian hyperstimulation syndrome (OHSS). Here, the authors report that estrildid finches naturally carry an analogous pathogenic mutation found in patients but avoid the syndrome by lowering a related receptor’s activity. Blocking this receptor successfully treats OHSS in mice.