FKBP52 deficiency–conferred uterine progesterone resistance is genetic background and pregnancy stage specific
Open accessAbstract
Immunophilin FKBP52 serves as a cochaperone to govern normal progesterone (P(4)) receptor (PR) function. Using Fkbp52(-/-) mice, we show intriguing aspects of uterine P(4)/PR signaling during pregnancy. Implantation failure is the major phenotype found in these null females, which is conserved on both C57BL6/129 and CD1 backgrounds. However, P(4) supplementation rescued implantation and subsequent decidualization in CD1, but not C57BL6/129, null females. Surprisingly, experimentally induced decidualization in the absence of blastocysts failed in Fkbp52(-/-) mice on either background even with P(4) supplementation, suggesting that embryonic signals complement uterine signaling for this event. Another interesting finding was that while P(4) at higher than normal pregnancy levels conferred PR signaling sufficient for implantation in CD1 null females, these levels were inefficient in maintaining pregnancy to full term. However, elevating P(4) levels further restored PR signaling to a level optimal for successful term pregnancy with normal litter size. Collectively, the results show that the indispensability of FKBP52 in uterine P(4)/PR signaling is a function of genetic disparity and is pregnancy stage specific. Since there is evidence for a correlation between P(4) supplementation and reduced risks of P(4)-resistant recurrent miscarriages and remission of endometriosis, these findings have clinical implications for genetically diverse populations of women.
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Female 52KO mice are infertile due to embryonic implantation and decidualization failure caused by progesterone insensitivity and uterine defects.
“The infertility is the result of embryonic implantation and decidualization failure due to progesterone insensitivity and uterine defects [6, 34, 35].”
From FKBP51 and FKBP52 in signaling and disease (2011) · cites this paper as [34]
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Cites
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The role of microRNAs in endometriosis and associated reproductive conditions
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- Authors
- Tranguch, S., Wang, H., Daikoku, T., Xie, H., Smith, D. F., & Dey, S. K.
- Affiliations
- Vanderbilt University Medical Center (US)
- Mayo Clinic (US)
- Corresponding author
- Dey, Sudhansu K.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-07-02
- Volume
- 117
- Issue
- 7
- Pages
- 1824-1834
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1888571
- OpenAlex
- W2164096066
- Cited by
- 121
- References
- 8
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 4 · 2019: 10 · 2018: 8 · 2017: 5 · 2016: 3 · 2015: 8 · 2014: 9 · 2013: 7 · 2012: 12
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- University of Virginia (U54-HD28934)
- Vanderbilt University Medical Center
- National Institute on Drug Abuse (F31DA021062)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK07563, DK 07563, DK-48218, R01DK048218, T32DK007563)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-033994, U54HD033994, R37HD012304, U54HD028934, R03HD050315, P30HD033994, HD050315, HD-12304, U54-HD-28934)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- FKBP52, progesterone receptor, progesterone resistance, implantation failure, decidualization, pregnancy stage, genetic background, C57BL/6J mice, ICR mice, progesterone supplementation, recurrent pregnancy loss, endometriosis
- MeSH terms
- Animals, Blastocyst, Drug Resistance, Embryo Transfer, Female, Pregnancy, Progesterone, Receptors, Progesterone, Uterus, Signal Transduction, Mice, Knockout, Tacrolimus Binding Proteins, Mice
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