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.

Cyclic Perimenstrual Pain and Discomfort and Australian Women's Associated Use of Complementary and Alternative Medicine: A Longitudinal Study.

OBJECTIVE: To examine the longitudinal change in Australian women's prevalence of cyclic perimenstrual pain and discomfort and the association between their symptoms and use of complementary and alternative medicine (CAM). METHOD: Data on endometriosis, premenstrual syndrome (PMS), irregular periods, heavy periods, and severe period pain were collected over a 7-year period from the Australian Longitudinal Study on Women's Health, for women aged 28 to 33 years in 2006, and at 3-year follow-ups. Changes in symptoms and patterns of CAM practitioner and therapy/product use associated with these symptoms were analyzed using longitudinal regression modeling. RESULTS: Over the 7-year period, prevalence rates of PMS and heavy periods increased, while prevalence rates of endometriosis, irregular periods, and severe period pain remained stable. The most common use of CAM longitudinally associated with the perimenstrual symptoms was use of vitamins/minerals, yoga/meditation, massage therapy, herbal medicine, and aromatherapy. Excluding consultation with a naturopath/herbalist, over the 7-year survey women's use of all other CAM practitioners increased as did their use of vitamin/minerals, yoga/meditation, and Chinese medicines, while aromatherapy use declined. CONCLUSION: Only the prevalence of PMS and heavy periods increased with aging in this sample of women. While overall use of CAM practitioner and self-prescribed products/therapies increased over time, CAM was chosen by women mainly to treat endometriosis and PMS. The extent to which this use reflects treatment efficacy is uncertain.

Serum heme oxygenase-1 levels in patients with primary dysmenorrhea.

PURPOSE: Primary dysmenorrhea effects the life-quality of women negatively. The aim of this study was to evaluate heme oxygenase-1 (HO1) activity together with malondialdehyde (MDA) and nitric oxide (NO) levels in patients with primary dysmenorrhea. METHODS: A total of 28 nulliparous women with the diagnosis of primary dysmenorrhea and 26 healthy controls were included in this study. On the first day of menstruation, all patients underwent ultrasound examination to exclude pelvic pathology and the visual analogue scale was applied to patients. Patient's visual analogue scale (VAS) scores, age, body mass index (BMI), menstrual cycle length (day), length of bleeding (day) were recorded. In the same day, fasting blood samples were taken from each patient for biochemical analysis. RESULTS: Serum MDA, NO and HO1 levels were found to be higher in women with primary dysmenorrhea compared to healthy controls (p = 0.012, p = 0.009, p < 0.001, respectively). There were no correlation among serum levels of HO1, NO and MDA, age, BMI, cycle length, pain score and menses duration in both groups. In Pearson's correlation analysis, positive correlation was found between HO1 levels with the NO levels (r = 0.316, p < 0.05) and VAS scores (r = 0.520, p < 0.01). Also, positive correlation was found between MDA levels and VAS scores (r = 0.327, p < 0.05). CONCLUSIONS: Serum HO1, NO and MDA levels increase in patients with primary dysmenorrhea. Antioxidant support might be helpful to reduce pain severity in primary dysmenorrhea.

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.

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.

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.

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.

Low-penetrance genes are associated with increased susceptibility to endometriosis.

OBJECTIVE: To investigate whether genetic polymorphisms of CYP1A1, GSTM1, and GSTT1 are associated with endometriosis. DESIGN: Genetic polymorphism analysis. SETTING: University department. PATIENT(S): A family with four women in two generations who had endometriosis and one member with suspected endometriosis in the third generation were compared with a group of fertile women. INTERVENTION(S): Laparoscopic examination. MAIN OUTCOME MEASURE(S): Blood specimens were obtained from fertile females and available affected female family members. Multiplex polymerase chain reaction (PCR) and restriction fragment length polymorphism PCR was done to determine each participant's genotype. RESULT(S): All affected family members had genotype CYP1A1 wt/m1 and GSTM1 null deletion. The frequency of this genotype in 54 fertile women was 13%. A 17-year-old family member with suspected endometriosis had the same genotype. One affected member was also a carrier of a GSTT1 null deletion. This combination was not found in any of the fertile participants. The most frequent genotypes in the sample were CYP1A1 wt/wt, with GSTM1 null deletion and at least one functional allele of GSTT1, and CYP1A1 wt/wt, with at least one functional allele of GSTM1 and GSTT1 (33% and 31%, respectively). CONCLUSION(S): The combination of CYP1A1 m1 polymorphism and GSTM1 null deletion is closely associated with penetration of the endometriosis phenotype, whereas GSTT1 null deletion may add to the penetration of this trait.

Prostaglandin synthase inhibitory activity in plasma of women with dysmenorrhea.

Prostaglandins have been implicated in the etiology of dysmenorrhea, and plasma levels of prostaglandin F metabolite are increased in women during dysmenorrhea episodes. We determined the prostaglandin synthase inhibitory activity of plasma obtained from the blood of women who experience moderate to severe dysmenorrhea. Blood was obtained at the onset of dysmenorrhea ("symptomatic") and during the late follicular phase of the ovarian cycle ("asymptomatic"). Prostaglandin synthase inhibitory activity in all samples was comparable to that previously found in adult women, and we found no difference in activity between the paired plasma samples, those obtained during symptomatic and asymptomatic times. Protein denaturation of the plasma by boiling also did not produce differences in prostaglandin synthase inhibition.