Recombinant FSH induced progesterone via partially regulating let-7 expression in human and mouse granulosa cells

The administration of recombinant follicle-stimulating hormone (rFSH) during in vitro fertilization (IVF) cycles in clinics may lead to premature progesterone rise, adversely affecting the success rates of assisted reproductive techniques. This study uncovers a potential mechanism through which rFSH stimulates progesterone production in human and mouse samples. Serum progesterone may increase prior to ovulation trigger in in vitro fertilization (IVF) patients, jeopardizing endometrial receptivity and therefore live birth rate. rFSH promotes progesterone production from human granulosa cells. Yet, the role of FSH in progesterone production needs deeper exploration. Studies were conducted in human primary cumulus cells from IVF cycles, a human granulosa cell line and mouse primary granulosa cells. The relative expression of Lethal-7 (let-7) was evaluated using real-time reverse transcription polymerase chain reaction (real-time RT-PCR). Human primary cumulus cells were collected from individual cumulus-oocyte complexes of high-progesterone patients (serum progesterone level higher than 5 nM, n = 18) and a control group (serum progesterone level less than 5 nM, n = 25). The expression of let-7a in human primary cumulus cells was markedly reduced in the high-progesterone group compared to the control. The serum progesterone level was augmented after rFSH treatment at doses of 0.5, 1 and 2.5 IU along with reduced expression of let-7a. Progesterone levels in the cultured medium from isolated mouse primary granulosa cells and the human granulosa cell line were significantly elevated with rFSH at 12.5, 25 and 50 IU/L concentrations, with decreased expression of let-7a. In addition, there was a robust increase in let-7a expression in the let-7a mimics-transfected group and a decrease in the let-7a inhibitor group with or without rFSH treatment, showing the opposite trend of progesterone. Collectively, our findings revealed the key role of let-7 in rFSH-induced progesterone levels in both human and mouse granulosa cells, providing a potential mechanism for premature progesterone rise.