Aberrant Immunoreactivity of Deoxyribonucleic Acid Methyltransferases in Adenomyosis

Abstract

Objectives: To investigate the expression and localization of deoxyribonucleic acid methyltransferases (DNMTs) in women with and without adenomyosis. Study Design: Ectopic and homologous eutopic endometrium from 50 women with adenomyosis and endometrium from 18 age- and menstrual phase-matched women without adenomyosis were used for immunohistochemical analysis. Tissue sections were immunostained with DNMT1, DNMT3A, and DNMT3B. Microscopic evaluation to assess the presence and localization of DNMT1, DNMT3A, and DNMT3B throughout the menstrual cycle in both eutopic endometrial and endometriotic tissues of women with adenomyosis was performed, and comparison with normal endometrium was made. Results: Compared with normal endometrium, immunoreactivity to DNMT1 and DNMT3B was higher in ectopic endometrium, while DNMT3A staining levels were significantly reduced in both eutopic and ectopic endometrium. DNMT1 immunoreactivity in eutopic endometrium was positively associated with heavier menses. Increased DNMT3B immunoreactivity in ectopic, but not eutopic, endometrium was associated with the severity of dysmenorrhea. Conclusions: The immunoreactivity to DNMTs in adenomyosis differs significantly from that in normal endometrium, suggesting that adenomyosis may be an epigenetic disease. The finding that DNMT3B correlates with the severity of dysmenorrhea suggests that DNMTs may be involved in adenomyosis-caused dysmenorrhea and its severity. Thus, therapeutics based on epigenetic rectification may hold promise in the management of adenomyosis.

Developmental Toxicant Exposure Is Associated with Transgenerational Adenomyosis in a Murine Model

“…Although the precise etiology of adenomyosis is unknown, this potentially invasive disease, like endometriosis, is estrogen dependent and frequently resolves after menopause [ 12 , 13 ]. Consequently, to advance our understanding of early events associated with the development of adenomyosis, several investigators have developed animal models of this disease using estrogenic compounds, such as tamoxifen [ 32 , 38 , 39 ] and toremifene [ 32 ]. Of note, following neonatal exposure of CD-1 mice to tamoxifen, Parrott et al [ 32 ] concluded that alteration and disorganization of the myometrial layer likely preceded, and perhaps facilitated, endometrial tissue invasion into the muscle.…”

“…Finally, the persistence of adenomyosis in the F3 generation, the first without direct toxicant exposure, strongly implicates epigenetic processes associated with the development of this disease. Indeed, several studies have demonstrated altered epigenetic marks as well as altered expression of epigenetic regulatory enzymes in women with adenomyosis compared with healthy women [ 9 , 11 , 38 , 49 ]. Although in our retrospective study we did not examine the epigenetic status of any gene, we have previously identified hypermethylation of the Pgr in association with development of the endometriosis-like uterine phenotype in mice exposed to TCDD either in utero (F1–F2) or ancestrally (F3) [ 8 ].…”

Uterine polyps, adenomyosis, leiomyomas, and endometrial receptivity

“…Increased E resistance also is associated with a down-regulation of P receptors and resulting P resistance (70,71) and decreased P receptor isoform B (72), perhaps related to methylation of the promoter (73). Overall this suggests that adenomyosis may be be related to epigenetic dysregulation of genes (73,74).…”

Effect of Adenomyosis on In Vitro Fertilization/Intracytoplasmic Sperm Injection Outcomes in Infertile Women: A Retrospective Cohort Study

“…Uterine adenomyosis is characterized by the presence of heterotypic endometrial glands and stroma in the myometrium, and it may be an epigenetic disease [1]. Recently, reports have focused on the relationship between adenomyosis and infertility, but with controversial conclusions and no consensus.…”