title: Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone.
abstract: One of the most widely accepted axioms of mammalian reproductive biology is that pregnancy requires the (sole) support of progesterone, acting in large measure through nuclear progesterone receptors (PRs) in uterine and cervical tissues, without which pregnancy cannot be established or maintained. However, mares lack detectable progesterone in the latter half of pregnancy. Instead of progesterone, several (mainly 5α-reduced) pregnanes are elevated and have long been speculated to provide progestational support in lieu of progesterone itself. To the authors' knowledge, evidence for the bioactivity of a second potent endogenously synthesized pregnane able to support pregnancy in the absence of progesterone has never before been reported. The 5α-reduced progesterone metabolite dihydroprogesterone (DHP) was shown in vivo to stimulate endometrial growth and progesterone-dependent gene expression in the horse at subphysiological concentrations and to maintain equine pregnancy in the absence of luteal progesterone in the third and fourth weeks postbreeding. Results of in vitro studies indicate that DHP is an equally potent and efficacious endogenous progestin in the horse but that the PR evolved with increased agonistic potency for DHP at the expense of potency toward progesterone based on comparisons with human PR responses. Sequence analysis and available literature indicate that the enzyme responsible for DHP synthesis, 5α-reductase type 1, also adapted primarily to metabolize progesterone and thereby to serve diverse roles in the physiology of pregnancy in mammals. Our confirmation that endogenously synthesized DHP is a biopotent progestin in the horse ends decades of speculation, explaining how equine pregnancies survive without measurable circulating progesterone in the last 4 to 5 mo of gestation.
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Scholtz
authors.forename: Shweta
authors.initials: S
authors.lastname: Krishnan
authors.forename: Barry A
authors.initials: BA
authors.lastname: Ball
authors.forename: C Jo
authors.initials: CJ
authors.lastname: Corbin
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Moeller
authors.forename: Scott D
authors.initials: SD
authors.lastname: Stanley
authors.forename: Karen J
authors.initials: KJ
authors.lastname: McDowell
authors.forename: Austin L
authors.initials: AL
authors.lastname: Hughes
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Conley
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D043582:5-alpha-Dihydroprogesterone / Q000097:blood / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006736:Horses; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D011247:Pregnancy / Q000378:metabolism*; D011374:Progesterone / Q000097:blood / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011980:Receptors, Progesterone / Q000819:agonists* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013045:Species Specificity; D053719:Tandem Mass Spectrometry
chemical_list: D011980:Receptors, Progesterone; D011374:Progesterone; D043582:5-alpha-Dihydroprogesterone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase
keywords: 5α DHP; 5α-pregnane-3,20-dione; endometrium; evolution; steroid