Chorioamnionitis and glucocorticoids elicit acute adverse effects on the developing ovine fetal ovaries

In brief: Preterm birth is frequently associated with antenatal corticosteroid treatment and intrauterine inflammation, yet their effect on fetal ovarian development remain largely unknown. Using a fetal sheep model, we demonstrate that these clinically relevant antenatal exposures induce distinct molecular and cellular alterations in the developing ovary, potentially compromising ovarian reserve establishment and subsequent female reproductive health. Abstract: Antenatal corticosteroid (ANS) therapy and chorioamnionitis are common antecedents of preterm birth, yet their effects on the developing fetal ovary remain poorly understood. Long-term follow-up of 45% of participants from the Auckland Steroid Trial reported that high-dose antenatal betamethasone exposure was associated with a modest delay in female reproductive maturation and a nonsignificant 2-year reduction in menopause age (Lord et al., 2025), raising concerns regarding potential effects on ovarian lifespan. Using a sheep model of pregnancy, we investigated the impact of antenatal betamethasone exposure and lipopolysaccharide-induced chorioamnionitis on fetal ovarian development. Date-mated Merino ewes were randomized to Saline Control, ANS, or chorioamnionitis treatment groups administered 2 or 8 days before delivery. Female lambs were delivered preterm at 124 ± 1 days' gestation, underwent standardized 30 min ventilation, and ovarian tissues were collected for transcriptomic and histological analyses. RNA sequencing demonstrated marked transcriptional alterations following both ANS and chorioamnionitis, affecting pathways involved in cell-cycle regulation, ovarian development, and cellular function. Histological assessment identified changes in follicle populations. Antenatal corticosteroid exposure was associated with increased markers of apoptosis, including significantly elevated terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Caspase-3 staining. Chorioamnionitis exposure resulted in significant reduction of primary follicle numbers, and trends toward increased tertiary and atretic follicles. Markers of ovarian and stromal cell populations were unchanged. Although limited by sample size and assessment of individual rather than combined exposures, these findings demonstrate that both ANS and chorioamnionitis induce acute molecular and structural changes in the developing fetal ovary, with potential implications for ovarian reserve, reproductive lifespan, and long-term female reproductive health.