Reproduction Abstracts

Some adult diseases are programmed in utero by fetal exposure to abnormal concentrations of steroid hormones. Threatened miscarriage in early pregnancy is treated by progesterone in many countries although robust evidence of efficacy is lacking. We hypothesised that increased progesterone concentrations may alter fetal development. In a small pilot study, using a pregnant sheep model, we administered 200 mg progesterone twice weekly from d20–d75 of gestation and collected fetuses at d75. We examined fetal pituitary by RT-PCR, maternal and fetal serum by ELISA and fetal testis by qRT-PCR and immunohistochemistry. Maternal plasma progesterone was not increased by progesterone administration, suggesting rapid clearance. However fetuses from mothers that were supplemented by progesterone had higher progesterone concentrations compared to controls (P=0.04) suggesting reduced clearance and augmented fetal exposure. There was no difference in the expression of LHB and PGR in the pituitary. The expression of AR, PGR, ESR1 and WT1 in the testis did not differ between the control and progesterone treated groups. Although the small numbers precluded statistical significance, there was a trend towards increased expression of AMH, INSL3, ESR2, LHCGR and STAR in the progesterone treated group. AR immunostaining, using blinded assessment, was consistently different in progesterone treated animals. We observed increased immunostaining intensity in the Sertoli cells and reduced immunostaining in the Leydig cells when compared to controls. Progesterone given to mothers crosses the placenta and is maintained in the fetal circulation. It could therefore exhibit direct and indirect effects on the fetus via progesterone receptors, its metabolism to other steroids or their displacement from serum proteins. This pilot study suggested the possibility of fetal testicular alterations and highlights need for further research into whether there is a lifelong legacy on offspring health as a result of therapeutic maternal progesterone administration in early pregnancy.