title: 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.
authors.affiliation: Institute of Maternal-Fetal Biology, and Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Konno
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Graham
authors.forename: Lea A
authors.initials: LA
authors.lastname: Rempel
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Ho-Chen
authors.forename: S M Khorshed
authors.initials: SM
authors.lastname: Alam
authors.forename: Pengli
authors.initials: P
authors.lastname: Bu
authors.forename: M A Karim
authors.initials: MA
authors.lastname: Rumi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Soares
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003338:Corpus Luteum / Q000187:drug effects / Q000378:metabolism*; D003656:Decidua / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007246:Infertility / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D011374:Progesterone / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D014599:Uterus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D011980:Receptors, Progesterone; D011374:Progesterone; D004958:Estradiol; D008156:Luciferases