Reduced endometrial expression of histone deacetylase 3 in women with adenomyosis who complained of heavy menstrual bleeding

Chenyu Mao; Xishi Liu; Sun-Wei Guo

doi:10.1016/j.rbmo.2023.103288

Reduced endometrial expression of histone deacetylase 3 in women with adenomyosis who complained of heavy menstrual bleeding

Reprod Biomed Online. 2023 Nov;47(5):103288. doi: 10.1016/j.rbmo.2023.103288. Epub 2023 Jul 15.

Authors

Chenyu Mao¹, Xishi Liu², Sun-Wei Guo³

Affiliations

¹ Department of General Gynaecology, Shanghai Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
² Department of General Gynaecology, Shanghai Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China.
³ Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China; Research Institute, Shanghai Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China. Electronic address: hoxa10@outlook.com.

PMID: 37690341
DOI: 10.1016/j.rbmo.2023.103288

Abstract

Research question: What role, if any, does histone deacetylase 3 (HDAC3) play in adenomyosis-associated heavy menstrual bleeding (HMB)?

Design: Seventy-two women with adenomyosis-associated HMB were recruited. Of these, 37 women reported moderate/heavy bleeding (MHB) and the remaining 35 women reported excessive bleeding (EXB). The stiffness of adenomyotic lesions and neighbouring endometrial-myometrial interface (EMI) was measured by transvaginal elastosonography, and full-thickness uterine tissue columns were processed for Masson trichrome staining and immunohistochemistry analyses. The protein expression levels of HDAC3 in endometrial cells cultured on substrates of different stiffnesses, and the protein concentrations of nuclear factor-κB (NF-κB) p65 subunit with HDAC3 suppression were evaluated. Mouse experiments were performed to assess the effect of adenomyosis on Hdac3 expression, endometrial repair and bleeding, and to evaluate the effect of HDAC3 inhibition on endometrial repair.

Results: Compared with controls, the endometrial staining of HDAC3 was significantly lower in women with adenomyosis-associated HMB, concomitant with a greater extent of fibrosis. The stiffness of lesions and neighbouring EMI was significantly higher in the EXB group compared with the MHB group, as was the extent of fibrosis in lesions, their neighboring EMI and endometrium. Expression of HDAC3 was reduced significantly when endometrial epithelial cells were cultured in stiff substrates. Suppression of HDAC3 abrogated the activation and signalling of NF-κB. Mice with induced adenomyosis exhibited reduced Hdac3 staining and elevated fibrosis in endometrium, concomitant with disrupted endometrial repair and more bleeding. Hdac3 inhibition resulted in botched inflammation and increased bleeding.

Conclusions: Lesional fibrosis results in reduced endometrial HDAC3 expression and subsequent disruption in NF-κB signalling and inflammation, leading to adenomyosis-associated HMB.

Keywords: Adenomyosis; Fibrosis; Heavy menstrual bleeding; Histone deacetylase 3; NF-κB; Stiffness.

MeSH terms

Adenomyosis* / pathology
Animals
Endometrium / metabolism
Female
Fibrosis
Humans
Inflammation / metabolism
Menorrhagia* / etiology
Mice
NF-kappa B / metabolism

Substances

histone deacetylase 3
NF-kappa B