Is primary dysmenorrhea a precursor of future endometriosis development?

Primary dysmenorrhea (PD) is the most common gynecologic disorder during adolescence and it is characterized by crampy lower abdominal pain that occurs during menstruation. Secondary dysmenorrhea, in contrast, has the same clinical features but occurs in women with a disease that could account for their symptoms (endometriosis, adenomyosis, uterine fibroids, pelvic inflammatory disease). Endometriosis is the most common cause of secondary dysmenorrhea and it should be considered in patients with persistent and clinically significant dysmenorrhea despite treatment. It is often diagnosed after a long delay, increasing the likelihood of pain chronicity and fertility problems at a later age. Women who suffer from dysmenorrhea in adolescence have higher risk of endometriosis in future. The open question is if endometriosis was already present at the onset of dysmenorrhea but undiagnosed or if PD favors subsequent development of endometriosis-associated pain. Since PD is associated with higher risk for developing chronic pain state and shares some of the same pain pathways of endometriosis (prostaglandins overproduction, inflammation, peripheral sensitization, central sensitization and abnormal stress responses), a correlation between PD and endometriosis is suggested. To know whether it is a risk factor for the development of endometriosis-associated pain may provide an opportunity for early intervention and prevention. The present review aims to investigate the clinical and pathogenetic features of PD and endometriosis in order to identify a possible association between the two conditions.

Inflammatory Markers in Dysmenorrhea and Therapeutic Options.

Dysmenorrhea often significantly reduces the quality of women's life and is still an important public health problem. Despite numerous studies, the pathomechanism of dysmenorrhea is not fully understood. Previous research indicates the complexity of biochemical reactions between the endocrine, vascular, and immune systems. Prostaglandins play a major role in the pathomechanism of dysmenorrhea. In contrast, cytokines and other proinflammatory factors in primary dysmenorrhea are less studied. In addition to the applied pharmacotherapy, more and more studies proving the effectiveness of non-pharmacological methods appear. Therefore, the present work contains a review of the latest research concerning factors involved in dysmenorrhea, as well as therapeutic options. In the literature search, authors used online databases, PubMed, and clinitrials.gov and browsed through individual gynecology, physiotherapy journals and books.

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.

Ginsenoside Rf alleviates dysmenorrhea and inflammation through the BDNF-TrkB-CREB pathway in a rat model of endometriosis.

To investigate the effects and the underlying mechanisms of ginsenoside Rf in a surgically induced rat endometriosis model, endometriosis was constructed through homologous transplantation and the Wistar rats were further randomly classified into the sham group, the estradiol valerate (E2V) control group, the endometriosis group, and the ginsenoside Rf groups (1.0, 2.0 and 4.0 mg kg-1, respectively). After 7 days of treatment, the implant volume and writhing responses were recorded. Vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α were analyzed using enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR) assay. Brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinases (TrkB), and phosphate-c-AMP-responsive element binding protein (pCREB) were further measured. Compared with the endometriosis group, ginsenoside Rf could decrease the volume of the endometriotic implants and writhing responses. Furthermore, the expression levels of VEGF and inflammation-related iNOS, IL-6, IL-1ß, and TNF-α were significantly down-regulated in the ginsenoside Rf groups in a dose-dependent manner. The results also showed that ginsenoside Rf could decrease the expression of BDNF, TrkB, and pCREB in the endometriotic implants. The alleviation of endometriosis-associated dysmenorrhea and inflammation by ginsenoside Rf may be partially mediated by the BDNF-TrkB-CREB pathway.

Estrogen is an important mediator of mast cell activation in ovarian endometriomas.

Endometriosis is an estrogen-dependent disease. Previous research has shown that abnormal enzymes associated with estrogen (E2) metabolism and an increased number of mast cells (MCs) in endometriomas are implicated in the pathogenesis of endometriosis. However, it remains unclear how MCs mediate the role of E2 in endometriosis. Accordingly, we investigated whether E2 was associated with the number of MCs, and the rate of degranulation, in local ovarian endometriomas, as well as the role of E2 on MCs during the pathogenesis of endometriosis. Using enzyme-linked immunosorbent assay and immunohistochemistry, we found that concentrations of E2, and the number and activity of MCs, were significantly higher in ovarian endometriomas than in controls, and that these parameters were correlated with the severity of endometriosis-associated dysmenorrhea. By measuring the release of hexosaminidase, we found that the rate of RBL2H3 cell degranulation increased after E2 treatment. Furthermore, activation of RBL2H3 cells by E2 was found to trigger the release of biologically active nerve growth factor, which promotes neurite outgrowth in PC12 cells and also sensitizes dorsal root ganglion cells via upregulation of Nav1.8 and transient receptor potential cation channel (subfamily V member 1) expression levels. When treated with E2, endometriotic cells could promote RBL2H3 cell recruitment by upregulating expression levels of stem cell factor, transforming growth factor-ß and monocyte chemoattractant protein-1; these observations were not evident with control endometrial cells. Thus, elevated E2 concentrations may be a key factor for degranulation and recruitment of MCs in ovarian endometriomas, which play a key role in endometriosis-associated dysmenorrhea.

Altered cytokine gene expression in peripheral blood monocytes across the menstrual cycle in primary dysmenorrhea: a case-control study.

Primary dysmenorrhea is one of the most common gynecological complaints in young women, but potential peripheral immunologic features underlying this condition remain undefined. In this paper, we compared 84 common cytokine gene expression profiles of peripheral blood mononuclear cells (PBMCs) from six primary dysmenorrheic young women and three unaffected controls on the seventh day before (secretory phase), and the first (menstrual phase) and the fifth (regenerative phase) days of menstruation, using a real-time PCR array assay combined with pattern recognition and gene function annotation methods. Comparisons between dysmenorrhea and normal control groups identified 11 (nine increased and two decreased), 14 (five increased and nine decreased), and 15 (seven increased and eight decreased) genes with ≥ 2-fold difference in expression (P<0.05) in the three phases of menstruation, respectively. In the menstrual phase, genes encoding pro-inflammatory cytokines (IL1B, TNF, IL6, and IL8) were up-regulated, and genes encoding TGF-ß superfamily members (BMP4, BMP6, GDF5, GDF11, LEFTY2, NODAL, and MSTN) were down-regulated. Functional annotation revealed an excessive inflammatory response and insufficient TGF-ß superfamily member signals with anti-inflammatory consequences, which may directly contribute to menstrual pain. In the secretory and regenerative phases, increased expression of pro-inflammatory cytokines and decreased expression of growth factors were also observed. These factors may be involved in the regulation of decidualization, endometrium breakdown and repair, and indirectly exacerbate primary dysmenorrhea. This first study of cytokine gene expression profiles in PBMCs from young primary dysmenorrheic women demonstrates a shift in the balance between expression patterns of pro-inflammatory cytokines and TGF-ß superfamily members across the whole menstrual cycle, underlying the peripheral immunologic features of primary dysmenorrhea.

Inflammatory pathways in endometrial disorders.

Complex interactions between the endocrine and immune systems govern the key endometrial events of implantation and menstruation. In contrast to other tissue sites, cyclical endometrial inflammation is physiological. However, dysregulation of this inflammatory response can lead to endometrial disorders. This review examines the inflammatory processes occurring in the normal endometrium during menstruation and implantation, highlighting recent advances in our understanding and gaps in current knowledge. Subsequently, the role of inflammatory pathways in the pathology of various common endometrial conditions is discussed, including heavy menstrual bleeding, dysmenorrhoea (painful periods), uterine fibroids, endometriosis and recurrent miscarriage.

Serum antiendometrial antibodies and diagnosis of endometriosis.

PROBLEM: The purpose of the present prospective multi-center study is to investigate the relationship between laparoscopic diagnosis of endometriosis and results of a serum antiendometrial antibody (AEA) assay. METHOD OF STUDY: Indirect immunofluorescence detection of AEA was performed on serum specimens from patients presenting with dysmenorrhea or chronic pelvic pain and infertility (n = 2609) utilizing frozen sections of endometrium acquired on cycle days 18-21 from normally cycling women without endometriosis. Diagnostic laparoscopy was performed within 1 year of AEA assay on 527 tested women. RESULTS: The relationship between the serum AEA and laparoscopic verification was characterized by a positive predictive value = 88%, negative predictive value = 86%, sensitivity = 87% and specificity = 87%. CONCLUSION: The AEA assay is a very good screening test for patients suspected of having endometriosis and should be utilized prior to laparoscopy in diagnostic categories of dysmenorrhea or chronic pelvic pain and infertility.

The use of serum CA-125 as a marker for endometriosis in patients with dysmenorrhea for monitoring therapy and for recurrence of endometriosis.

BACKGROUND: To estimate the value of CA-125 for the diagnosis of endometriosis in women with dysmenorrhea, as well as its significance in monitoring therapy and follow-up. METHODS: One hundred and fifty-seven women undergoing laparoscopy for dysmenorrhea were prospectively studied for serum CA-125 concentration. For those with advanced endometriosis receiving danazol treatment after conservative surgery, CA-125 was also determined every month during medication and once every 12 months after treatment. RESULTS: The sensitivity and specificity of serum CA-125 for the diagnosis of endometriosis were 61.1% and 87.5% respectively. Elevated CA-125 (>35 U/ml) was noted in 65/75 cases (86.70%) with advanced endometriosis, but in only 15/56 patients (26.8%) with minimal and mild endometriosis. Although there were significantly higher CA-125 levels in unmarried women, and a negative correlation (r=-0.1970, p=0.0284) between CA-125 and parity, there was no statistical difference in incidence of endometriosis by the status of marriage or parity. Ten women with advanced endometriosis were found with persistent endometriosis by laparoscopy during danazol treatment, even though they tested with normal CA-125 levels (<35 U/ml) at that time. Fifteen patients had elevated CA-125 levels before and one year after therapy, and were confirmed with recurrence of endometriosis by laparoscopy. Nine women with elevated CA-125 levels before treatment, were found without recurrence of endometriosis and had normal CA-125 levels one year after therapy. CONCLUSION: For endometriosis, CA-125 is a valuable adjuvant in the follow-up of recurrence in patients with advanced endometriosis and initially elevated CA-125 levels. It is not an effective screening tool for patients with dysmenorrhea, or for monitoring therapy. There was no significant correlation between the development of endometriosis and reproductive factors.

Mitogen-induced lymphocyte proliferation and peripheral blood mononuclear cell beta-endorphin concentrations in primary dysmenorrhoea.

Dysmenorrhoea is a recurrent painful disease which causes physical and psychological stress. The purpose of the present study was to investigate whether there was a measurable derangement of immune cells and immune responses in women with severe primary dysmenorrhoea. On day 26 of one cycle and on days 1 and 3 of the following cycle we measured polyclonal, mitogen-induced lymphocyte proliferation and beta-endorphin concentration in peripheral blood mononuclear cells obtained from 16 infertile women with normal pelvis, of whom eight had and eight did not have the disorder. In women with dysmenorrhoea, polyclonal mitogen-induced lymphocyte proliferation was lower than in controls on all 3 days considered, but the difference was statistically significant only on day 26 (43,605 +/- 9876 micrograms/ml versus 67,305 +/- 15,249 micrograms/ml; P < 0.01). Monocyte beta-endorphin concentrations in the patients with dysmenorrhoea were significantly elevated on day 3 compared to controls (67.8 +/- 24.3 pg/10(6) cells versus 29.7 +/- 6.9 pg/10(6) cells; P < 0.05). Our results demonstrate that immune responses are modified in patients with primary dysmenorrhoea. These effects are independent of circulating hormone concentrations and are consistent with the role of dysmenorrhoea as a stressful event.