Role of SIRT1 and Progesterone Resistance in Normal and Abnormal Endometrium

Tae Hoon Kim, Steven L. Young, Tsutomu Sasaki, Jeffrey L Deaton, David P Schammel, Wilder A. Palomino, Wilder Alberto Palomino, Jae‐Wook Jeong, Bruce A. Lessey
The Journal of clinical endocrinology and metabolism · 2021 · vol. 107(3) , pp. 788–800 · doi:10.1210/clinem/dgab753 · PMID:34665857 · W3206972336
article OA: bronze CC0 ⤵ 19 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This study found that SIRT1 expression, normally present during menses or implantation, is overexpressed in endometriosis and contributes to progesterone resistance and infertility.

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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.

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Condition tags

mesh:D004715endometriosisinfertility

MeSH descriptors

Endometriosis Endometrium Infertility, Female Sirtuin 1 Uterine Diseases Adult Animals Carbazoles Carbazoles Carbazoles Case-Control Studies Disease Models, Animal Embryo Implantation Embryo Implantation Endometriosis Endometriosis Endometriosis Endometrium Endometrium Endometrium

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Cited by (19)

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