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

Publication ,  Journal Article
Scholtz, EL; Krishnan, S; Ball, BA; Corbin, CJ; Moeller, BC; Stanley, SD; McDowell, KJ; Hughes, AL; McDonnell, DP; Conley, AJ
Published in: Proc Natl Acad Sci U S A
March 4, 2014

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.

Duke Scholars

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 4, 2014

Volume

111

Issue

9

Start / End Page

3365 / 3370

Location

United States

Related Subject Headings

  • Tandem Mass Spectrometry
  • Species Specificity
  • Sequence Analysis, DNA
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Progesterone
  • Real-Time Polymerase Chain Reaction
  • Progesterone
  • Pregnancy
  • Molecular Sequence Data
  • Immunohistochemistry
 

Citation

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Scholtz, E. L., Krishnan, S., Ball, B. A., Corbin, C. J., Moeller, B. C., Stanley, S. D., … Conley, A. J. (2014). Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone. Proc Natl Acad Sci U S A, 111(9), 3365–3370. https://doi.org/10.1073/pnas.1318163111
Scholtz, Elizabeth L., Shweta Krishnan, Barry A. Ball, C Jo Corbin, Benjamin C. Moeller, Scott D. Stanley, Karen J. McDowell, Austin L. Hughes, Donald P. McDonnell, and Alan J. Conley. “Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone.Proc Natl Acad Sci U S A 111, no. 9 (March 4, 2014): 3365–70. https://doi.org/10.1073/pnas.1318163111.
Scholtz EL, Krishnan S, Ball BA, Corbin CJ, Moeller BC, Stanley SD, et al. Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3365–70.
Scholtz, Elizabeth L., et al. “Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone.Proc Natl Acad Sci U S A, vol. 111, no. 9, Mar. 2014, pp. 3365–70. Pubmed, doi:10.1073/pnas.1318163111.
Scholtz EL, Krishnan S, Ball BA, Corbin CJ, Moeller BC, Stanley SD, McDowell KJ, Hughes AL, McDonnell DP, Conley AJ. Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3365–3370.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 4, 2014

Volume

111

Issue

9

Start / End Page

3365 / 3370

Location

United States

Related Subject Headings

  • Tandem Mass Spectrometry
  • Species Specificity
  • Sequence Analysis, DNA
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Progesterone
  • Real-Time Polymerase Chain Reaction
  • Progesterone
  • Pregnancy
  • Molecular Sequence Data
  • Immunohistochemistry