Subfertility Linked to Combined Luteal Insufficiency and Uterine Progesterone Resistance

• Published in: Endocrinology (Philadelphia) 2010-09, Vol.151 (9), p.4537-4550
• Main Authors: Konno, Toshihiro, Graham, Amanda R, Rempel, Lea A, Ho-Chen, Jennifer K, Alam, S. M. Khorshed, Bu, Pengli, Rumi, M. A. Karim, Soares, Michael J
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Animals; Base Sequence; Biological and medical sciences; Cell Line, Tumor; Cells, Cultured; Corpus Luteum - drug effects; Corpus Luteum - metabolism; Decidua; Decidua - metabolism; Developmental stages; Estradiol - pharmacology; Female; Fertility; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation, Developmental; Humans; Infertility - genetics; Infertility - metabolism; Litter size; Luciferases - genetics; Luciferases - metabolism; Male; Ovulation; Phenotypes; Placenta; Pregnancy; Progesterone; Progesterone - blood; Progesterone - metabolism; Progesterone - pharmacology; Promoter Regions, Genetic - genetics; Rats; Rats, Inbred BN; Rats, Inbred Dahl; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; Resistance factors; Sequence Analysis, DNA; Sex hormones; Stromal Cells - cytology; Stromal Cells - metabolism; Uterus; Uterus - cytology; Uterus - drug effects; Uterus - metabolism; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-0440

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 17β-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. The Brown Norway rat exhibits luteal insufficiency and uterine progesterone resistance, which profoundly affect its ability to reproduce.