FKBP52 deficiency–conferred uterine progesterone resistance is genetic background and pregnancy stage specific
Susanne Tranguch, … , David F. Smith, Sudhansu K. Dey
Susanne Tranguch, … , David F. Smith, Sudhansu K. Dey
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1824-1834. https://doi.org/10.1172/JCI31622.
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Research Article Endocrinology

FKBP52 deficiency–conferred uterine progesterone resistance is genetic background and pregnancy stage specific

Abstract

Immunophilin FKBP52 serves as a cochaperone to govern normal progesterone (P4) receptor (PR) function. Using Fkbp52–/– mice, we show intriguing aspects of uterine P4/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, P4 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 P4 supplementation, suggesting that embryonic signals complement uterine signaling for this event. Another interesting finding was that while P4 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 P4 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 P4/PR signaling is a function of genetic disparity and is pregnancy stage specific. Since there is evidence for a correlation between P4 supplementation and reduced risks of P4-resistant recurrent miscarriages and remission of endometriosis, these findings have clinical implications for genetically diverse populations of women.

Authors

Susanne Tranguch, Haibin Wang, Takiko Daikoku, Huirong Xie, David F. Smith, Sudhansu K. Dey

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Figure 1

P4 supplementation via Silastic implants rescues implantation failure in CD1 Fkbp52–/– females.

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P4 supplementation via Silastic implants rescues implantation failure in...
Ovulation (A) and fertilization (B) were examined on day 2 of pregnancy. The number of ovulated eggs was not significantly different in WT and Fkbp52–/– (KO) females. Values are mean ± SEM; P > 0.05, unpaired Student’s t test. Fertilization rate was determined by counting the number of 2-cell embryos after flushing oviducts. Numbers above the bars indicate the total number of 2-cell embryos per total number of eggs recovered. The fertilization rate was comparable between WT and KO females (P > 0.05; unpaired Student’s t test). (C) Implantation fails in KO females but is rescued by P4 as examined on day 5 of pregnancy. Implants containing P4 were inserted s.c. in KO females (KO+P4) on day 2 of pregnancy. Representative photographs of uteri with or without ISs as demarcated by blue bands in WT, KO, and KO+P4 mice are shown. Representative photographs of blastocysts recovered from uteri of KO females without IS. Arrowheads and short arrows indicate the location of ovaries and ISs, respectively. The long arrow indicates the uterus from which unimplanted blastocysts were recovered. Scale bar: 50 μm.