# Primary Uterine Inertia (PUI) in Dogs Is Associated with Impaired Placental Availability of Factors Involved in the Parturition Cascade

## TL;DR

This study finds that primary uterine inertia in dogs may result from impaired placental signaling involving progesterone and glucocorticoid pathways, leading to difficult labor.

## Contribution

The study identifies disrupted placental hormonal signaling as a potential cause of primary uterine inertia in dogs.

## Key findings

- PUI placentae show reduced PGF2α synthase and increased prostaglandin transporter, impairing PGF2α activity.
- PUI placentae have increased PGR levels but unchanged decidual cell numbers.
- GR/NR3C1 levels and placental cortisol-to-cortisone conversion are reduced in PUI.

## Abstract

In dogs, the parturition is initiated by decreased progesterone (P4) signaling in the placenta, mediated through its receptor, PGR, located in the maternal part of the placenta (decidual cells). This leads to increased production of PGF2α in fetal placental cells (trophoblasts), inducing luteolysis and placentolysis (i.e., the breakdown of the corpus luteum and placental function), and triggering uterine contractions. Glucocorticoids (e.g., cortisol) appear to contribute to the initiation of parturition by affecting P4-PGR signaling through the glucocorticoid receptor (GR/NR3C1). The underlying causes of primary uterine inertia (PUI), a common cause of dystocia (difficult labor) in dogs, are unclear. This study compared placentae from dogs with PUI to those undergoing normal prepartum luteolysis (LUT) to investigate whether abnormal placental signaling could contribute to PUI. PUI placentae had no major changes in the prostaglandin-related enzymes (PTGS2, PTGES, HPGD), but had reduced expression of PGF2α synthase (PGFS/AKR1C3) and increased prostaglandin transporter (PGT), indicating impaired PGF2α activity. PGR was increased, although the number of maternal decidual cells remained unchanged. GR/NR3C1 levels were lower in PUI. In conclusion, PUI may be associated with disrupted hormonal signaling in the placenta involving the P4-PGR and glucocorticoid pathways, resulting in impaired parturition in dogs.

The canine parturition cascade involves decreased placental progesterone (P4) signaling mediated through its nuclear receptor PGR in decidual cells, leading to increased trophoblast production of PGF2α that promotes luteolysis, placentolysis, and myometrial contractility. A local role for glucocorticoids in initiating parturition through increased placental availability of cortisol and glucocorticoid receptor (GR/NR3C1), possibly affecting P4-PGR signaling, has been suggested. Primary uterine inertia (PUI) is a major cause of canine dystocia, but its pathophysiology remains unclear. Here, we hypothesized that dysregulated placental signaling could contribute to PUI. The availability of parturition cascade-related factors was assessed in placentae of dogs with PUI and during physiological prepartum luteolysis (LUT). Compared with LUT, PUI had no significant changes in prostaglandin-related factors PTGS2, PTGES, and HPGD (p > 0.05), but had lower PGF2α synthase PGFS/AKR1C3 (p < 0.001), and higher PGT abundance (p < 0.001). PUI had increased PGR transcript and protein levels (p < 0.001), but the same number of decidual cells (p > 0.05). GR/NR3C1 availability was reduced in PUI (p < 0.05), along with decreased placental cortisol-to-cortisone conversion. Our findings suggest that PUI could be associated with disturbances of the parturition cascade, possibly due to inadequate P4-PGR and glucocorticoid signaling in the placenta.