Luteal phase defect is a major cause of female infertility, as steroidogenesis by the corpus luteum is essential for establishment of pregnancy. The EGFR ligand amphiregulin is known to improve steroidogenesis, specifically StAR expression and P4 production, in human granulosa-lutein (hGL) cells, but it remains unclear whether HB-EGF, another EGFR ligand that regulates luteal function, exerts similar effects. To find out, researchers recently analyzed steroidogenesis in the KGN cell line and primary cultured hGL cells from patients undergoing IVF. The HB-EGF receptors EGFR and HER4 and their potential dimerization partner HER2 were expressed in both cell types and treatment with HB-EGF induced StAR expression in KGN and hGL cells without altering the expression of several steroidogenesis- related enzymes in KGN cells. Inhibition and knockdown experiments revealed that EGFR and HER4 were required for HB-EGF-induced enhancement of StAR expression and P4 production, while HER2 was not and that the effects of HB-EGF treatment were mediated by ERK1/2 signaling activation. Although in vivo studies are needed, the findings increase understanding of the role of HB-EGF in the corpus luteum and may help inform future treatments for infertility caused by corpus luteum deficiency.