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Proceedings of the National Academy of Sciences of the United States of America2014; 111(9); 3365-3370; doi: 10.1073/pnas.1318163111

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.
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Publication Date: 2014-02-18 PubMed ID: 24550466PubMed Central: PMC3948269DOI: 10.1073/pnas.1318163111Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research explores the peculiar case of horses, which unlike most mammals, don’t rely solely on progesterone hormone for maintaining pregnancies. The study identifies the 5α-reduced progesterone metabolite dihydroprogesterone (DHP) as a hormone that can support horse pregnancies, even in the absence of progesterone.

Understanding the Pregnancy Hormones

  • Progesterone is generally considered essential in mammal pregnancies, working through nuclear progesterone receptors (PRs) in the uterus and cervix. Without it, pregnancies typically cannot be established or maintained.
  • Surprisingly, horses show almost no trace of progesterone in the latter half of their pregnancies. Instead, several pregnanes (a class of steroid hormones), predominantly in their 5α-reduced forms, are elevated.

Role of Dihydroprogesterone (DHP) in Equine Pregnancies

  • The research establishes for the first time that an endogenously synthesized pregnane, DHP, can support pregnancy in the absence of progesterone.
  • In vivo trials showed that even subphysiological concentrations of DHP manage to stimulate endometrial growth and the expression of progesterone-dependent genes in horses. This is particularly significant in the third and fourth weeks post-breeding, when luteal progesterone (produced in the corpus luteum of the ovary) is absent.
  • In vitro studies confirmed that DHP has the same progestational potency and efficacy as progesterone in horses. However, the progesterone receptors seem to have evolved to favour DHP over progesterone.

Evidence from Sequence Analysis

  • The team’s sequence analysis points to the enzyme 5α-reductase type 1 being responsible for the synthesis of DHP. This enzyme appears to have adapted primarily to metabolize progesterone, playing a diverse role in the physiology of mammalian pregnancies.

Conclusion: Role of DHP in Horse Pregnancies Confirmed

  • The research provides confirmation that endogenously produced DHP is a potent progestin hormone in horses. This discovery backs up speculation that’s been ensuing for decades on how equine pregnancies are sustained without the presence of circulating progesterone in the final four or five months.

Cite This Article

APA
Scholtz EL, Krishnan S, Ball BA, Corbin CJ, Moeller BC, Stanley SD, McDowell KJ, Hughes AL, McDonnell DP, Conley AJ. (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

Publication

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
NlmUniqueID: 7505876
Country: United States
Language: English
Volume: 111
Issue: 9
Pages: 3365-3370

Researcher Affiliations

Scholtz, Elizabeth L
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616.
Krishnan, Shweta
    Ball, Barry A
      Corbin, C Jo
        Moeller, Benjamin C
          Stanley, Scott D
            McDowell, Karen J
              Hughes, Austin L
                McDonnell, Donald P
                  Conley, Alan J

                    MeSH Terms

                    • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics
                    • 5-alpha-Dihydroprogesterone / blood
                    • 5-alpha-Dihydroprogesterone / metabolism
                    • Analysis of Variance
                    • Animals
                    • Base Sequence
                    • Chromatography, High Pressure Liquid
                    • Female
                    • Horses
                    • Humans
                    • Immunohistochemistry
                    • Molecular Sequence Data
                    • Pregnancy / metabolism
                    • Progesterone / blood
                    • Progesterone / metabolism
                    • Real-Time Polymerase Chain Reaction
                    • Receptors, Progesterone / agonists
                    • Receptors, Progesterone / metabolism
                    • Reverse Transcriptase Polymerase Chain Reaction
                    • Sequence Analysis, DNA
                    • Species Specificity
                    • Tandem Mass Spectrometry

                    Grant Funding

                    • R01 DK048807 / NIDDK NIH HHS
                    • R37 DK048807 / NIDDK NIH HHS
                    • DK048807 / NIDDK NIH HHS

                    Conflict of Interest Statement

                    The authors declare no conflict of interest.

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                    Citations

                    This article has been cited 7 times.
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