Correlation of LOX­5 and COX­2 expression with inflammatory pathology and clinical features of adenomyosis.

Adenomyosis is a common benign disease of women of childbearing age. The typical clinical features are prolonged menstruation, menorrhagia and ingravescent dysmenorrhea. In the present study, the severity of dysmenorrhea was assessed using the visual analogue scale system as follows: 0, No pain; 1­3, minimal pain; 4­6, moderate pain; and 7­10, severe pain. Menstrual blood loss was evaluated using the pictorial blood loss assessment chart (PBAC). Menorrhagia was defined as excessive menstrual blood loss >80 ml (PBAC >100) per period. Specimens of eutopic endometrium (EU) and ectopic endometrium (EC) were collected from 20 patients with adenomyosis to evaluate the association between lipoxygenase­5 (LOX­5) and cyclooxygenase 2 (COX­2) and inflammatory pathology and clinical features of adenomyosis. For that purpose, the expression levels of LOX­5, COX­2, interleukin (IL)­6 and IL­8 in the EU and EC of patients with adenomyosis were determined, and clinical data including dysmenorrhea and menstruation were analyzed. Differences in expression levels of LOX­5 and COX­2 were detected, and the correlations between LOX­5, COX­2, IL­6 and IL­8 in different groups were analyzed. In addition, the correlations between LOX­5, COX­2 and clinical features of adenomyosis were investigated. The present study demonstrated that LOX­5 and COX­2 are overexpressed in EU and EC, and they have positive correlations with IL­6 and IL­8, suggesting that adenomyosis lesions are present in inflammatory pathological conditions. The expression levels of LOX­5 and COX­2 exhibited a correlation with dysmenorrhea and menstruation.

Expression Levels of Myostatin and Matrix Metalloproteinase 14 mRNAs in Uterine Leiomyoma are Correlated With Dysmenorrhea.

Uterine leiomyoma is the most common benign neoplasm of female reproductive system, found in about 50% of women in reproductive age. The mechanisms of leiomyoma growth include cell proliferation, which is modulated by growth factors, and deposition of extracellular matrix (ECM). Activin A and myostatin are growth factors that play a role in proliferation of leiomyoma cells. Matrix metalloproteinases (MMPs) are known for their ability to remodel the ECM in different biological systems. The aim of this study was to evaluate the expression levels of activin ßA-subunit, myostatin, and MMP14 messenger RNAs (mRNAs) in uterine leiomyomas and the possible correlation of these factors with clinical features of the disease. Matrix metalloproteinase 14 was highly expressed in uterine leiomyoma and correlated with myostatin and activin A mRNA expression. Moreover, MMP14 and myostatin mRNA expression correlated significantly and directly with the intensity of dysmenorrhea. Overall, the present findings showed that MMP14 mRNA is highly expressed in uterine leiomyoma, where it correlates with the molecular expression of growth factors and is further increased in cases of intense dysmenorrhea.

Aberrant immunoreactivity of deoxyribonucleic acid methyltransferases in adenomyosis.

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.

Elevated immunoreactivity against class I histone deacetylases in adenomyosis.

BACKGROUND/AIMS: Adenomyosis is a common condition with a poorly understood pathogenesis. Recent data suggest that it may be an epigenetic disease. This study investigated the expression and localization of class I histone deacetylases (HDACs) in women with and without adenomyosis. METHODS: The ectopic and homologous eutopic endometrium of 50 women with adenomyosis and the endometrium of 18 age- and menstrual phase-matched women without adenomyosis were used for immunohistochemical analysis. Tissue sections were immunostained with HDAC1, -2, and -3. Microscopic evaluation to assess the presence and localization of HDAC1-3 throughout the menstrual cycle in both eutopic endometrial and endometriotic tissues of women with adenomyosis was performed and compared with the normal endometrium. RESULTS: We found that, compared with the normal endometrium, immunoreactivity against HDAC1 and HDAC3 was higher in both the eutopic and the ectopic endometrium. Increased HDAC2 in the eutopic endometrium was found to be associated with the severity of dysmenorrhea. CONCLUSION: Given the potential wide-ranging effect of histone deacetylation on gene expression, these findings suggest that HDACs may be involved in adenomyosis. They also suggest the possibility that HDAC2 may be involved in dysmenorrhea and its severity and that HDACs may be potential therapeutic targets in adenomyosis.

Expression of tyrosine kinase receptor B in eutopic endometrium of women with adenomyosis.

OBJECTIVE: Our study is to investigate whether tyrosine kinase receptor B (TrkB) is expressed in eutopic endometrium of women with adenomyosis and its association with clinical characteristics. METHODS: We collected endometrial tissues from 31 women with adenomyosis and 30 adenomyosis-free women undergoing surgery for benign indications. TrkB expression was assessed by immunohistochemistry and reverse-transcription polymerase chain reaction. RESULTS: Immunoreactive staining for TrkB was present as brown flocculent precipitate in the endometrial cells. The average level of TrkB protein (quantitation of immunostaining intensity) in secretory endometrial samples of women with adenomyosis was significantly higher than that in controls (p < 0.01). The average level of TrkB messenger RNA (mRNA) expression of women with adenomyosis was significantly higher than that of controls at secretory phase (p < 0.01). In addition, the immunostaining quantitation of TrkB protein was positively correlated with the serum CA125 (r = 0.308, p = 0.016) and dysmenorrhea (r = 0.393, p = 0.002). CONCLUSIONS: Our study revealed elevation of TrkB protein and mRNA expression in the secretory endometrium of women with adenomyosis. Moreover, TrkB protein expression in human endometrium was positively correlated with the serum CA125 and dysmenorrhea. TrkB might contribute to the pathogenesis and progression of adenomyosis.

Alteration of focal adhesion kinase expression in eutopic endometrium of women with endometriosis.

OBJECTIVE: To investigate whether focal adhesion kinase (FAK) expression is altered in eutopic endometrium of women with endometriosis. DESIGN: Experimental study using human endometrial tissue. SETTING: Academic research center. PATIENT(S): Women with or without endometriosis who were undergoing surgery for benign indications. INTERVENTION(S): Endometrial biopsy. MAIN OUTCOME MEASURE(S): Expression of FAK was assessed by immunohistochemistry, Western blotting analysis, and reverse-transcription polymerase chain reaction. RESULT(S): At secretory phase, the average level of endometrial FAK expression of women with endometriosis was significantly higher than that of controls, but no significant difference was found between the two groups at proliferative phase. There was a positive correlation between FAK expression in secretory endometrial tissues and disease stage and pelvic pain in women with endometriosis. Furthermore, the endometrial FAK protein expression varied with the serum E(2) at proliferative phase and with the ratio of E(2) to P at secretory phase. CONCLUSION(S): The study showed a significant increase of FAK expression in the secretory endometrial tissues of women with endometriosis, a relationship between FAK expression and disease stage, pelvic pain, and serum steroid hormones. Those results suggest that FAK may play a role in the pathogenesis of endometriosis and be regulated by steroid hormones.

A pilot study on the off-label use of valproic acid to treat adenomyosis.

Following on the heels of the discovery that endometriosis is an epigenetic disease, we conducted a pilot study on the off-label use of valproic acid to treat adenomyosis. We found that by the end of the 3-month treatment, all three recruited patients reported complete disappearance of dysmenorrhea, with an average of one-third reduction in uterus size.

COX-2 inhibitors and their role in gynecology.

UNLABELLED: This review summarizes current knowledge about the roles of cyclooxygenases and prostaglandins in reproductive medicine. With the development of COX-2 specific inhibitors, new therapeutic options are available to obstetricians and gynecologists, offering better-tolerated alternatives to conventional NSAIDs. The analgesic effectiveness of COX-2 specific inhibitors is well established, and they are already in use in a range of painful conditions. Both celecoxib and valdecoxib are indicated for the treatment of primary dysmenorrhea, and may be effective in postoperative pain, including hysterectomy, and pain associated with endometriosis. There is also speculation that COX-2 specific inhibitors may be effective tocolytic agents without the risks to the fetus seen with conventional NSAIDs. The role of COX-2 in oncogenesis is also under investigation, and COX-2 specific inhibitors may eventually be used in the prevention and treatment of gynecologic malignancies. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to describe the two types of cylooxygenase enzymes (COX), to list the effects and side effects of NSAIDs and COX-2 medications, and to outline the various changes in COX expression during pregnancy.