Subfertility Linked to Combined Luteal Insufficiency and Uterine Progesterone Resistance

Abstract

Early pregnancy loss is common and can be caused by a range of factors. The Brown Norway (BN) rat exhibits reproductive dysfunction characterized by small litter size and pregnancy failure and represents a model for investigating early pregnancy loss. In this study, we investigated the establishment of pregnancy in the BN rat and gained insight into mechanisms causing its subfertility. Early stages of BN uteroplacental organization are unique. The BN primordial placenta is restricted in its development and correlates with limited BN uterine decidual development. BN uterine decidua was shown to be both structurally and functionally distinct and correlated with decreased circulating progesterone (P4) levels. Ovarian anomalies were also apparent in BN rats and included decreased ovulation rates and decreased transcript levels for some steroidogenic enzymes. Attempts to rescue the BN uterine decidual phenotype with steroid hormone therapy were ineffective. BN uteri were shown to exhibit reduced responsiveness to P4 but not to 17beta-estradiol. P4 resistance was associated with decreased transcript levels for the P4 receptor (Pgr), a P4 receptor chaperone (Fkbp4), and P4 receptor coactivators (Ncoa1 and Ncoa2). In summary, the BN rat exhibits luteal insufficiency and uterine P4 resistance, which profoundly affects its ability to reproduce.

BMPR2 is required for postimplantation uterine function and pregnancy maintenance

“…Since the uterine lumen remains in the decidual zone of E9 implantation sites and artificial decidualization suggests a defect in decidual cell proliferation, we examined decidual cell proliferation and cell cycle regulation in pregnant Bmpr2 cKO female mice. We first analyzed mRNA for Prl3c1 and Prl8a2, markers for decidual cell differentiation (27,28), in isolated decidual tissues from E9 control and Bmpr2 cKO uteri (Supplemental Figure 7B) and found attenuation of these transcripts in uteri of pregnant Bmpr2 cKO mice ( Figure 4A). MKI67-positive cells in both MD and AMD compartments at E9 were also decreased by >50% (Figure 4, B and C).…”

Chromosome-substituted rat strains provide insights into the genetics of placentation

“…The latter diet was used for comparisons with HSD rats. Pregnancy parameters are similar for BN rats fed either the low-salt or standard laboratory diets (18,19).…”

“…Strain-specific patterns of placentation are evident in the rat (12,18,19). The Holtzman Sprague-Dawley (HSD) outbred and ACI, Fischer 344 (F344), and Dahl salt-sensitive (DSS) inbred strains exhibit robust placentation, including a welldeveloped junctional zone and extensive intrauterine trophoblast invasion (19).…”

“…In contrast placentation in the Brown Norway (BN) rat is more restrictive (19). The BN rat junctional zone is reduced in size and intrauterine trophoblast invasion is shallow, resulting in a placental insufficiency that adversely affects fetal growth and the success of pregnancy (12,18,19). These observations suggest that a genetic approach for investigating the regulation of placentation may be possible.…”

“…Given that BN and DSS rat strains possess distinctive placentation phenotypes (18,19), the purpose of this study was to use the DSS-BN chromosome-substituted panel to elucidate genetic insights about the regulation of placentation. We identified a trait associated with placentation [junctional zone expression of prolactin family 5 subfamily a, member 1 (Prl5a1)] showing quantitative differences between BN and DSS parent strains.…”