Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone

Elizabeth L. Scholtz, Shweta Krishnan, Barry A. Ball, C. Jo Corbin, Benjamin Moeller, Scott D Stanley, Karen J. McDowell, Austin L. Hughes, Donald P. McDonnell, Alan J Conley

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3365-3370
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number9
DOIs
StatePublished - Mar 4 2014

Fingerprint

20-alpha-Dihydroprogesterone
Progesterone Receptors
Horses
Progesterone
Pregnancy
Pregnanes
Progestins
Corpus Luteum
Cytoplasmic and Nuclear Receptors
Sequence Analysis
Mammals

Keywords

  • 5α DHP
  • 5α-pregnane-3,20-dione
  • Endometrium
  • Evolution
  • Steroid

ASJC Scopus subject areas

  • General

Cite this

Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone. / Scholtz, Elizabeth L.; Krishnan, Shweta; Ball, Barry A.; Corbin, C. Jo; Moeller, Benjamin; Stanley, Scott D; McDowell, Karen J.; Hughes, Austin L.; McDonnell, Donald P.; Conley, Alan J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 9, 04.03.2014, p. 3365-3370.

Research output: Contribution to journalArticle

Scholtz, Elizabeth L. ; Krishnan, Shweta ; Ball, Barry A. ; Corbin, C. Jo ; Moeller, Benjamin ; Stanley, Scott D ; McDowell, Karen J. ; Hughes, Austin L. ; McDonnell, Donald P. ; Conley, Alan J. / Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 9. pp. 3365-3370.
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