Female mutant restricted ovulator (RO) chickens of the White Leghorn strain carry a naturally occurring single nucleotide mutation in the very low density lipoprotein receptor (VLDLR) gene. Due to this mutation, RO hens fail to express a functional VLDLR protein on the oocyte membrane, which results in an impaired uptake of circulating yolk precursor macromolecules. Mutant RO hens subsequently develop hyperlipidemia and generally fail to lay eggs due to follicular atresia. Since RO hens also reportedly have three-fold higher basal plasma estrogen concentrations, combined with four-fold lower levels of circulating progesterone as compared to wild-type (WT) hens, we hypothesized that RO hens would have an increased abundance of pituitary progesterone receptor (PR) mRNA and PR isoforms A and B as well as alterations in circulating gonadotrophin levels. Quantitative PCR assays revealed significantly greater (P<or=0.05) pituitary PR mRNA abundance in RO hens as compared to WT hens. Similarly, pituitary PR isoforms A and B quantities were significantly greater (P<or=0.05) in the RO hens compared to WT hens. In addition, mutant RO hens had significantly greater plasma concentrations of luteinizing hormone, follicle stimulating hormone, estrone, and estradiol, but lower circulating progesterone levels. Collectively, elevated circulating estrogen and/or decreased progesterone levels may have contributed to the upregulation of PR mRNA and PR isoforms A and B in the RO hen pituitary gland. Lastly, in order to gain a more complete understanding of why RO hens are reproductively dysfunctional, a model is proposed that links humoral and ovarian factors to observed and putative changes in the hypothalamic-pituitary axis.