Relaxin and Maternal Lactocrine Programming of Neonatal Uterine Development

In mammals, including the pig (Sits scrofa domesticus), structural patterning and functional programming of uterine tissues involve events that occur shortly after birth. Porcine endometrial development between birth (postnatal day 0 [PND 0]) and PND 15 is estrogen receptor (ER) dependent and estrogen sensitive. The endometrium is relaxin (RLX) receptor (RXFP1) positive and ERa negative at birth. Uterine expression of RXFP1 and ERa, detectable by PND 2, increases with age from PND 0 to 14. Estrogen exposure during this period sufficient to affect uterine developmental trajectory and adult uterine phenotype also alters uterine RXFP1 gene expression patterns in the neonatal uterus. Data implicate RXFP1 as an element of the uterine developmental program. Uterotrophic effects documented for both estrogen and RLX in the neonatal pig are age-specific and most pronounced after onset of ERa expression. Patterns of inhibition of RLX effects on uterine development induced with ICI 182,780, an ER antagonist, indicate that cross talk between RLX and estrogen signaling systems evolve with age in the porcine uterus. Given that RLX administered from birth stimulates uterine ER alpha expression and that estrogen administered from birth stimulates RXFP1 expression by PND 2, a feed-forward relationship between these signaling systems is envisioned. Evidence that RLX is present in porcine milk and in the circulation of nursing offspring supports the lactocrine hypothesis for maternal programming of uterine tissues in which milk-borne RLX, acting via RXFP1, sustains Er alpha expression and porcine endometrial development in the neonate.