Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Observational Study
. 2022 Feb 17;107(3):788-800.
doi: 10.1210/clinem/dgab753.

Role of SIRT1 and Progesterone Resistance in Normal and Abnormal Endometrium

Tae Hoon Kim  1 , Steven L Young  2 , Tsutomu Sasaki  3 , Jeffrey L Deaton  4 , David P Schammel  5 , Wilder Alberto Palomino  6 , Jae-Wook Jeong  1 , Bruce A Lessey  4
Affiliations
Observational Study

Role of SIRT1 and Progesterone Resistance in Normal and Abnormal Endometrium

Tae Hoon Kim et al. J Clin Endocrinol Metab. .

Erratum in

Abstract

Context: Progesterone resistance, a known pathologic condition associated with a reduced cellular response to progesterone and heightened estrogen responses, appears to have a normal physiologic role in mammalian reproduction. The molecular mechanism responsible for progesterone resistance in normal and abnormal endometrium remains unclear.

Objective: To examine the roles of sirtuin-1 (SIRT1) in normal endometrium as well as endometrium associated with infertility and endometriosis, as an epigenetic modulator associated with progesterone resistance.

Methods: SIRT1 expression was examined by Western blot, quantitative real-time polymerase chain reaction, and immunohistochemistry in mouse uterus and human endometrium. Mice with uterine specific Sirt1 overexpression were developed to examine SIRT1's role in endometrial function and endometriosis development. EX-527, a SIRT1 inhibitor, and SRT1720, a SIRT1 agonist, were also used to evaluate SIRT1 effect on endometriosis.

Results: In normal healthy women, endometrial SIRT1 is expressed only during menses. SIRT1 was dramatically overexpressed in the endometrium from women with endometriosis in both the epithelium and stroma. In mice, SIRT1 is expressed at the time of implantation between day 4.5 and 5.5 of pregnancy. Overexpression of SIRT1 in the mouse uterus leads to subfertility due to implantation failure, decidualization defects and progesterone resistance. SIRT1 overexpression in endometriotic lesions promotes worsening endometriosis development. EX-527 significantly reduced the number of endometriotic lesions in the mouse endometriosis model.

Conclusions: SIRT1 expression and progesterone resistance appears to play roles in normal endometrial functions. Aberrant SIRT1 expression contributes to progesterone resistance and may participate in the pathophysiology of endometriosis. SIRT1 is a novel and targetable protein for the diagnosis as well as treatment of endometriosis and the associated infertility seen in this disease.

Keywords: endometriosis; endometrium; epigenetics; implantation; infertility; progesterone.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Overexpression of sirtuin-1 (SIRT1) in the menstrual tissue from women and a mouse model of menstruation. (A) The expression of SIRT1 proteins was examined by immunohistochemistry at proliferative (a and e), secretory (b and f), menses (c and g), and without primary antibody (d and h) tissues from women without endometriosis (a-d) and in women with endometriosis (e-h). The quantification data of immunohistochemistry SIRT1 in human. (B) The schematic diagrams for mouse menstrual model. The expression of SIRT1 at gestation day (GD) 2.5 (a), GD 3.5 (b), menstrual-like tissues of mouse (c), and without primary antibody (d). The quantification data of immunohistochemistry SIRT1 in mouse. The data represents the mean ± standard error of the mean. ***P < 0.001. Abbreviations: Endo Sec, endometrium from secretory phase; Endo Prolif, endometrium from proliferative phase.
Figure 2.
Figure 2.
Uterus-specific overexpression of Sirt1 causes implantation failure and decidualization defect. The overexpression of sirtuin-1 (SIRT1)was evaluated in the uteri of control and Sirt1Over at gestation day (GD) 3.5 by quantitative real-time polymerase chain reaction (A) and immunohistochemical analysis and quantification data of SIRT1 positive cell (B). (C) The implantation failure was observed in Sirt1Over mice at GD 7.5. (D) The schematic diagrams for artificial decidualization and gross anatomy of artificially induced decidualized uteri of control (a) and Sirt1Over (b) mice. There was a significant decrease in stimulated and unstimulated (control) horn weight ratio in Sirt1Over mice as compared with control. The data represent the mean ± standard error of the mean. **P < 0.01.
Figure 3.
Figure 3.
Uterus-specific overexpression of Sirt1 results in nonreceptive endometrium due to progesterone resistance. (A) Immunohistochemical analysis of Ki67 proteins and (B) quantification data of Ki67-positive cells at gestation day (GD) 3.5 in endometrium of control (a) and Sirt1Over (b) mice. Quantitative real-time polymerase chain reaction analysis of (C) estrogen receptor 1 target genes (Muc-1, Clca3, Ltf) at gestation day (GD) 3.5 and (D) progesterone receptor target (PGR) genes (Fst, Klf15, Patch1, Gli1) in uteri of control and Sirt1Over mice at GD 3.5. (E) The interaction between sirtuin-1 and progesterone receptor A. (F) Immunohistochemical analysis of PGR proteins and (G) HSCORE of PGR at GD 3.5 in endometrium of control (a) and Sirt1Over (b) mice. The results represent the mean ± standard error of the mean. ***P < 0.001; **P < 0.01; *P < 0.05.
Figure 4.
Figure 4.
Endometriosis induces sirtuin-1 (SIRT1) overexpression in the eutopic endometrium and Sirt1 overexpression in endometriotic lesion results in an increase of endometriosis development. (A) The expression of SIRT1 was significantly increased in mouse endometriosis (Eosis) group compared to sham group. (B) SIRT1 agonist-treated endometriosis (Pgrcre/+Rosa26mTmG/+) mice (SRT1720) showed a significant increase of ectopic sites compared to vehicle-treated endometriosis (Pgrcre/+Rosa26mTmG/+) mice. (C) Autologous induction of endometriosis in Sirt1Over mice showed an increase of number of ectopic sites compared to control. The results represent the mean ± standard error of the mean. ***P < 0.001; *P < 0.05.
Figure 5.
Figure 5.
EX-527 restores implantation failure in Sirt1Over mice and suppresses endometriosis development in mouse. (A) EX-527 treatment at dose of 2.5 mg/kg rescued an implantation failure observed in Sirt1Over mice. (B) EX-527 at dose of 0.5 mg/kg treatment did not harm female reproduction functions in wild-type female mice. (C) EX-527 treatment at dose of 0.5 mg/kg reduced the development of endometriotic sites in mouse endometriosis model. The results represent the mean ± standard error of the mean. **P < 0.01.
Figure 6.
Figure 6.
Proposed model for sirtuin-1 function in progesterone resistance of endometriosis.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Bulun SE, Yilmaz BD, Sison C, et al. . Endometriosis. Endocr Rev. 2019;40(4):1048-1079. - PMC - PubMed
    1. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389-2398. - PMC - PubMed
    1. Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN. Progesterone resistance in endometriosis: origins, consequences and interventions. Acta Obstet Gynecol Scand. 2017;96(6):623-632. - PubMed
    1. Bulun SE, Cheng YH, Yin P, et al. . Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006;248(1-2):94-103. - PubMed
    1. Simpson HW, McArdle CS, Griffiths K, Turkes A, Beastall GH. Progesterone resistance in women who have had breast cancer. Br J Obstet Gynaecol. 1998;105(3):345-351. - PubMed

Publication types

MeSH terms

Supplementary concepts