Plasma proteins and persistent postsurgical pelvic pain among adolescents and young adults with endometriosis.

BACKGROUND: Noninvasive biomarkers that predict surgical treatment response would inform personalized treatments and provide insight into potential biologic pathways underlying endometriosis-associated pain and symptom progression. OBJECTIVE: To use plasma proteins in relation to the persistence of pelvic pain following laparoscopic surgery in predominantly adolescents and young adults with endometriosis using a multiplex aptamer-based proteomics biomarker discovery platform. STUDY DESIGN: We conducted a prospective analysis including 142 participants with laparoscopically-confirmed endometriosis from the Women's Health Study: From Adolescence to Adulthood observational longitudinal cohort with study enrollment from 2012-2018. Biologic samples and patient data were collected with modified World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project tools. In blood collected before laparoscopic ablation or excision of endometriosis, we simultaneously measured 1305 plasma protein levels, including markers for immunity, angiogenesis, and inflammation, using SomaScan. Worsening or persistent postsurgical pelvic pain was defined as having newly developed, persistent (ie, stable), or worsening severity, frequency, or persistent life interference of dysmenorrhea or acyclic pelvic pain at 1-year postsurgery compared with presurgery. We calculated odds ratios and 95% confidence intervals using logistic regression adjusted for age, body mass index, fasting status, and hormone use at blood draw. We applied Ingenuity Pathway Analysis and STRING analysis to identify pathophysiologic pathways and protein interactions. RESULTS: The median age at blood draw was 17 years (interquartile range, 15-19 years), and most participants were White (90%). All had superficial peritoneal lesions only and were treated by excision or ablation. One-year postsurgery, pelvic pain worsened or persisted for 76 (54%) of these participants with endometriosis, whereas pelvic pain improved for 66 (46%). We identified 83 proteins associated with worsening or persistent pelvic pain 1-year postsurgery (nominal P<.05). Compared with those with improved pelvic pain 1-year postsurgery, those with worsening or persistent pelvic pain had higher plasma levels of CD63 antigen (odds ratio, 2.98 [95% confidence interval, 1.44-6.19]) and CD47 (odds ratio, 2.68 [95% confidence interval, 1.28-5.61]), but lower levels of Sonic Hedgehog protein (odds ratio, 0.55 [95% confidence interval, 0.36-0.84]) in presurgical blood. Pathways related to cell migration were up-regulated, and pathways related to angiogenesis were down-regulated in those with worsening or persistent postsurgical pelvic pain compared with those with improved pain. When we examined the change in protein levels from presurgery to postsurgery and its subsequent risk of worsening or persistent postsurgical pain at 1-year follow-up, we observed increasing levels of Sonic Hedgehog protein from presurgery to postsurgery was associated with a 4-fold increase in the risk of postsurgical pain (odds ratio [quartile 4 vs 1], 3.86 [1.04-14.33]). CONCLUSION: Using an aptamer-based proteomics platform, we identified plasma proteins and pathways associated with worsening or persistent pelvic pain postsurgical treatment of endometriosis among adolescents and young adults that may aid in risk stratification of individuals with endometriosis.

Altered sleep and diurnal consequences in women with dysmenorrhea: study from the EPISONO database.

PURPOSE: Our study aimed to identify alterations in sleep, inflammatory mediators, fatigue and quality of life in women with dysmenorrhea and compare them to women without dysmenorrhea. METHODS: The sample comprised 328 women from a Brazilian cross-sectional sleep study, EPISONO (2007), who had undergone 1-night polysomnography (PSG) type I and completed questionnaires related to sleep quality, daytime sleepiness, insomnia, fatigue, anxiety, depression, and quality of life. Blood samples were used to assess levels of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP). The 2 groups were distributed based on the presence or absence of dysmenorrhea symptoms. RESULTS: Sleep efficiency was significantly lower in the group of women with dysmenorrhea (82.5% ± 13.8) compared to the non-dysmenorrhea group (86.2% ± 10.9). Dysmenorrhea was associated with significantly higher scores of fatigue and worse scores in the physical quality of life. No statistical differences were detected in inflammatory markers between the 2 groups. DISCUSSION: Fatigue and physical quality of life were presented in women with dysmenorrhea, as was reduced sleep efficiency, although no alteration on inflammatory markers were observed. CONCLUSION: These findings show that dysmenorrhea can have a deleterious effect on women's sleep, with repercussions on daily routines and quality of life.

Comparative pharmacokinetics study of leonurine and stachydrine in normal rats and rats with cold-stagnation and blood-stasis primary dysmenorrhoea after the administration of Leonurus japonicus houtt electuary.

Leonurus japonicus houtt, a well-known herb of traditional Chinese medicine, is widely used to treat gynaecological diseases. In this study, a rapid and sensitive liquid chromatography with tandem mass spectrometry method for simultaneously quantifying leonurine and stachydrine, the two main bioactive components in Leonurus japonicus houtt, was developed and validated. Plasma samples were prepared by protein precipitation with acetonitrile and separation by a Hewlett Packard XDB-C8 column (150 × 4.6 mm, id, 5 µm) equipped with a gradient elution system containing methanol-water and 0.1% formic acid at a flow-rate of 0.4 mL/min. Components were then detected by a mass spectrometer in positive electrospray ionization mode. This method showed good linearity, precision, accuracy, recovery, stability, and negligible matrix effects, which were within acceptable ranges. The method was successfully applied to compare the pharmacokinetics in normal rats and rats with cold-stagnation and blood-stasis primary dysmenorrhoea treated with Leonurus japonicus houtt electuary. The result showed significant differences (p < 0.05) in the pharmacokinetic parameters between the primary dysmenorrhoea and normal groups. This result implied that Leonurus japonicus houtt electuary remained longer and was absorbed slower in rats with primary dysmenorrhoea and exhibited higher bioavailability and peak concentration.

The impact of circulating 25-hydroxyvitamin and oral cholecalciferol treatment on menstrual pain in dysmenorrheic patients.

This study aims to determine Vitamin-D level in patients with primary dysmenorrhea and investigate the effect of Vitamin-D replacement on symptoms. About 100 patients in the 18-30 age group followed-up with primary dysmenorrhea diagnosis were included in this observational study. The pain severity was assessed using the visual analog scale (VAS). 25-hydroxy vitamin D(25(OH)D) levels of the patients were measured and the replacement therapy was applied according to measurement results. The patients were followed for three months in total. At the end of the three-month period, the 25(OH)D level was measured and the VAS score was assessed once more after the therapy. 25(OH)D level was insufficient in 23.0%, deficient in 45.0%, and severely deficient in 32.0% of the patients. It was found that the VAS score increased as the 25(OH)D level decreased (r = -0.320; p = .002). A significant reduction was observed in VAS scores after Vitamin-D treatment in all three groups; the amount of reduction in VAS score was determined to be higher in the patients with severely deficient levels of 25(OH)D, compared to the patients with deficient or insufficient levels (p < .001). A significant and negative correlation was found between Vitamin-D and symptoms associated with dysmenorrhea in our study. The Vitamin-D replacement therapy led to a significant decrease in symptoms.

Markers of lipid and protein peroxidation among Nigerian university students with dysmenorrhea.

INTRODUCTION: Oxidative stress has been associated with primary dysmenorrhea, but studies that have assessed multiple markers of peroxidation are scarce. This study investigated malondialdehyde (MDA), nitrotyrosine (3-NT), and protein carbonyls (PrCarb) as markers of oxidative stress and antioxidant status by serum alpha tocopherol level in young Nigerian women with dysmenorrhea. MATERIALS AND METHODS: In a case-control design, 45 female undergraduates who had had regular menses for at least six previous cycles were recruited consecutively from a university clinic as cases and 45 apparently healthy age-matched counterparts in their hall of residences as controls. Serum levels of MDA, 3-NT, and PrCarb were determined using standard methods, and the values were compared between cases and controls using Mann-Whitney U-test and graphs. RESULTS: Study participants' ages range from 16 to 29 years (mean = 22.0 ± 3.1 years). Serum level of 3-NT (45.89 ± 37.11 vs 21.27 ± 13.94 ng/mL) and MDA (0.75 ± 0.19 vs 0.45 ± 0.11 nmol/mL) was significantly higher in cases than controls. Plasma alpha tocopherol was significantly lower in cases (7.51 ± 1.95 µmol/L) than controls (8.98 ± 1.95 µmol/L). Conversely, PrCarb levels were not significantly difference between cases and controls. There were significant correlations between alpha tocopherol and 3-NT (r = -0.285; P = 0.007) and MDA (r = -0.321; P = 0.002), whereas this relationship was not shown with PrCarb (r = -0.073; P = 0.496). CONCLUSION: Remarkable lipid and protein peroxidation observed in young Nigerian women with dysmenorrhea was accompanied by correspondingly low level of serum alpha tocopherol suggesting potential need for vitamin E supplementation.

Altered white matter microarchitecture in the cingulum bundle in women with primary dysmenorrhea: A tract-based analysis study.

Primary dysmenorrhea (PD), as characterized by painful menstrual cramps without organic causes, is associated with central sensitization and brain function changes. Previous studies showed the integrated role of the default mode network (DMN) in the pain connectome and its key contribution on how an individual perceives and copes with pain disorders. Here, we aimed to investigate whether the cingulum bundle connecting hub regions of the DMN was disrupted in young women with PD. Diffusion tensor imaging was obtained in 41 PD patients and 41 matched healthy controls (HC) during their periovulatory phase. The production of prostaglandins (PGs) was obtained in PD patients during their pain-free and pain phases. As compared with HC, PD patients had similar scores of pain intensity, anxiety, and depression in their pain-free phase. However, altered white matter properties mainly located in the posterior section of the cingulum bundle were observed in PD. Besides PGs being related to menstrual pain, a close relationship was found between the white matter properties of the cingulum bundle during the pain-free phase and the severity of the menstrual pain in PD patients. Our study suggested that PD had trait changes of white matter integrities in the cingulum bundle that persisted beyond the time of menstruation. We inferred that altered anatomical connections may lead to less-flexible communication within the DMN, and/or between the DMN and other pain-related brain networks, which may result in the central susceptibility to develop chronic pain conditions in PD's later life. Hum Brain Mapp 38:4430-4443, 2017. © 2017 Wiley Periodicals, Inc.

Effect of Bushenwenyanghuayu decoction on nerve growth factor and bradykinin/bradykinin B1 receptor in a endometriosis dysmenorrhea mouse model.

OBJECTIVE: To observe the effects of Bushenwenyanghuayu decoction (BD), a Traditional Chinese Medicine (TCM), on the serum concentration of nerve growth factor (NGF) and bradykinin (BK), and protein and mRNA levels of NGF and bradykinin B1 receptor (BKB1R) in a mouse model of endometriosis dysmenorrhea. METHODS: Seventy-five experimental female BALB/c mice were randomly divided into five groups, 15 mice each: sham, model, BD high dose (61.67 g/kg), BD low dose (15.42 g/kg), and gestrinone (0.4 mg/kg) groups. All the mice except for those in the sham group underwent auto-transplantation surgery and were gavaged estradiol valerate (0.5 mg/kg, daily for 12 days) after surgery. On the 12th day, 1 h after administration, writhing response was induced by intraperitoneal injection of oxytocin at 2 U/mouse. The writhing frequency and latency were recorded and the volume of the ectopic foci was measured. The concentration of serum NGF and BK was detected by enzyme-linked immunosorbent assay, the protein expression of NGF and BKB1R was tested by immunohistochemistry and western blotting, and NGF and BKB1R mRNAs were detected by real-time PCR. RESULTS: Compared with the model group, the volume of the ectopic foci in the treatment groups was significantly lower (P < 0.01), the writhing frequency was decreased (P < 0.05), and the writhing latency was prolonged (P < 0.01). Compared with the sham group, serum NGF and BK levels in the model group were significantly increased (P < 0.01). There were positive correlations for writhing frequency among the NGF and BK groups (P < 0.01). The serum NGF and BK levels were significantly lower in the treatment groups than the model group (P < 0.05). The protein expression of NGF, BKB1R was significantly decreased in the treatment groups compared with the model group (P < 0.01). NGF and BKB1R mRNA expression was significantly decreased in the treatment groups compared with the model group (P < 0.01). CONCLUSION: NGF and BK/BKB1R may play an important role in the development of endometriosis-associated dysmenorrhea, and BD was found to inhibit the development of endometriosis and relieve dysmenorrhea by influencing NGF and BK/ BKB1R mRNA and protein levels.

Plasma metabolic profiling of normal and dysmenorrhea syndrome rats and the effects of Xiang-Fu-Si-Wu Decoction intervention.

CONTEXT: Primary dysmenorrhea (PDM), a common, clinically heterogeneous endocrine disorder affecting young women, is associated with endocrinopathy and metabolic abnormalities. The Xiang-Fu-Si-Wu Decoction (XFSWD) is a traditional Chinese medicine preparation used to treat PDM. OBJECTIVE: In the current study, a plasma metabonomics method based on the ultra-high-performance liquid chromatography-quantitative time-of-flight-mass spectrometry (UHPLC-Q-TOF-MS) system was employed to examine the mechanism of XFSWD action in PDM. MATERIALS AND METHODS: Estradiol benzoate (0.01 g/kg/d) and oxytocin (5 mL/kg) were used to create the dysmenorrhea rat model. Based on the chromatographic data of plasma samples at different time-points following oral administration of XFSWD mixed in water (37.8 g crude herbs/kg) on day 7, partial least square (PLS) and discriminate analysis (DA) were applied to visualize group differentiation and marker selection. RESULTS: Systemic changes occurring in PDM reflect alterations in not only uterus function but also whole-body metabolism. The XFSWD was effective as a therapeutic agent for PDM by reflect metabolic pathway. Prostaglandins and lysophospholipids were identified as two marker types for oxytocin-induced dysmenorrhea syndrome, including LysoPC(18:4), LysoPE(22:2/0:0), LysoPC(17:0), PGJ2, 11-deoxy-11-methylene-PGD2, 15-deoxy-δ-12,14-PGJ2, LysoPC(20:3), etc. Specifically, the concentrations of prostaglandins compounds (PGJ2, 11-deoxy-11-methylene-PGD2, 15-deoxy-δ-12,14-PGJ2) were increased while those of lysophospholipid compounds [lysoPC(18:4), LysoPE(22:2/0:0), LysoPC(17:0)] were decreased to a significant extent (p < 0.05) in dysmenorrheal rats. Upon treatment with the XFSWD at 12 h, the concentrations of lysophospholipids showed no significant differences (P > 0.05) between the model and normal groups. The lysophospholipid levels were restored. Lysophospholipids were the key factors in phospholipid metabolism. Thus, disruption of phospholipids metabolism appears critical for the development of dysmenorrhea. The XFSWD exerted its effects by interfering with the sphingolipid metabolic pathway. DISCUSSION AND CONCLUSIONS: The metabonomics method presents a promising tool to treat PDM in animal models, and may be applicable for clinical treatment of the human disease in the future.

Metabolomic study of biochemical changes in the plasma and urine of primary dysmenorrhea patients using UPLC-MS coupled with a pattern recognition approach.

Primary dysmenorrhea (PD) is characterized by painful menstrual cramps without any organic pathology and has a prevalence of up to 90% in adolescents. Recent advances in its etiology and pathogenesis are providing more speculative hypotheses focused on integral systems. Using a targeted tandem mass spectrometry (MS/MS)-based metabolomic platform, we explored the changes of metabolic profiling in plasma/urine simultaneously between PD patients and healthy controls before and after a 3-month herbal medicine (namely Shaofu Zhuyu formula concentrated-granule, SFZYFG) therapy. To detect and identify potential biomarkers associated with PD and SFZYFG treatment, we also performed a combined UPLC-QTOF-MS/MS-based metabolomic profiling of the plasma/urine samples, indicating a further deviation of the patients' global metabolic profile from that of controls. The total thirty-five metabolites (nineteen in plasma and sixteen in urine), up-regulated or down-regulated (p < 0.05 or 0.01), were identified and contributed to PD progress. These promising identified biomarkers underpinning the metabolic pathway including sphingolipid metabolism, steroid hormone biosynthesis, and glycerophospholipid metabolism are disturbed in PD patients, which were identified by using pathway analysis with MetPA. Twenty-four altered metabolites and fourteen biochemical indicators were restored back to the control-like level after the treatment of SFZYFG and could be potential biomarkers for monitoring therapeutic efficacy. These findings may be promising to yield a valuable insight into the pathophysiology of PD and to advance the approaches of treatment, diagnosis, and prevention of PD and related syndromes.

Pain levels associated with renal colic and primary dysmenorrhea: a prospective controlled study with objective and subjective outcomes.

OBJECTIVES: To evaluate the degree of pain associated with renal colic and primary dysmenorrhea using objective and subjective measurements. METHODS: In total, 60 subjects participated in this study. There were 20 subjects in the renal colic group (average age 24.45 ± 2.35 years), 20 subjects in the primary dysmenorrhea group (average age 23.75 ± 1.86 years), and 20 subjects in the control group (average age 24.20 ± 2.57 years). The serum chromogranin A (CgA) values were determined by an enzyme-linked immunosorbent assay and the mean pain score was assessed by means of a Visual Analog Scale (VAS) for each individual. RESULTS: The serum CgA level was 19.83 ± 19.61 ng/ml for the renal colic group, 13.45 ± 8.52 ng/ml for the primary dysmenorrhea group and 12.45 ± 7.76 ng/ml for the control group. The mean VAS score for pain was 7.95 ± 1.54 for the renal colic group and 7.05 ± 1.50 for the primary dysmenorrhea group. CONCLUSIONS: Primary dysmenorrheic pain is as intense as renal colic pain. Emergency room physicians should display the same degree of care and attention for the treatment of patients with primary dysmenorrhea as they do for patients with renal colic, and rapidly initiate an effective treatment for these patients.

[Effect of massage on hemodynamics parameters of uterine artery and serum prostaglandin in treating patients with primary dysmenorrhea].

OBJECTIVE: To observe the curative effect of massage in the treatment of primary dysmenorrhea (PD), and its effect on hemodynamics parameters of uterine artery and serum prostaglandins. METHODS: 60 PD patients were randomly assigned to the massage group and the control group, 30 in each. Patients in the massage group received massage, while those in the control group orally took ibuprofen sustained release capsule, both for three menstrual cycles. The pain degree was assessed using visual analogue scale (VAS). The hemodynamics parameters of uterine artery [including pulsatility index (PI), resistance index (RI), systolic to diastolic peak ratio (S/D)], the serum levels of prostaglandin F2alpha (PGF2alpha) and PGE2 in the menstruation were detected in the two groups before and after treatment. RESULTS: There was no statistical difference in each index before treatment between the two groups (P>0.05). Compared with the control group after treatment, the scores of VAS (mm, 33. 17+/-7.93 vs 63.53+/-9.48), PI (2.18+/-0.18 vs 2.74+/-0.23), RI (0.67+/-0.09 vs 0. 86+/-0.27), S/D (5.44+/-0.47 vs 7.56+/-0.28), and serum PGF2a level (ng/L, 28. 10+/-2.41 vs 37.68+/-2.16) were lower and serum PGE, level (ng/L, 29.82+/-2.13 vs 26.43+/-1.42) higher in the massage group, showing statistical difference (P<0.05, P<0.01). CONCLUSIONS: Massage had favorable therapeutic effect on PD. Its effect might be achieved through improving the blood circulation of uterus, adjusting the abnormal levels of PGF2a and PGE2, thus exerting pain relief effect.

[Correlation between blood-stasis tongue figure and platelet activating factor (PAF) and acetyl hydrolase of PAF (PAF-AH) in patients with primary dysmenorrhea].

OBJECTIVE: To explore the pathologic mechanism of blood-stasis tongue figure (BSTF) formation in patients with primary dysmenorrhea. METHODS: Blood levels of platelet activating factor (PAF) and acetyl hydrolase of PAF (PAF-AH) in 41 patients with primary dysmenorrhea and 20 healthy subjects were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: The level of PAF in the 22 patients with BSTF was 252. 214 +/- 37. 568 ng/L, which was higher than that in patients without BSTF (19 patients, 212.348 +/- 22.794 ng/L) and healthy subjects (182.126 +/- 18.306 ng/L) respectively, while level of PAF-AH showed an opposite sequence in them, i.e., 3.090 +/- 1.483, 5.382 +/- 1.873, and 5.607 +/- 2.073 ng/L, respectively (P < 0.05). Patients without BSTF showed only a higher level of PAF when compared with that in healthy subjects (P < 0.05). No significant difference in PAF or PAF-AH levels was shown among patients with BDTF of different Chinese medical syndrome types (P > 0.05). CONCLUSION: PAF level obviously increased and PAF-AH level obviously decreased in primary dysmenorrhea patients of BSTF, suggesting that the imbalance of PAF and PAF-AH was correlated with the pathologic mechanism of the BSTF formation in primary dysmenorrhea patients.

An integrated study of metabolomics and transcriptomics to reveal the anti-primary dysmenorrhea mechanism of Akebiae Fructus.

ETHNOPHARMACOLOGICAL RELEVANCE: Akebiae Fructus, a Tujia minority folk medicine and a well-known traditional Chinese medicine for soothing the liver, regulating Qi, promoting blood circulation and relieving pain, is widely used in the treatment of primary dysmenorrhea. However, little is known about its underlying mechanism. AIM OF THE STUDY: To explore the effect of Akebiae Fructus on primary dysmenorrhea model induced by estradiol benzoate and oxytocin, and to provide better understanding of the mechanism of Akebiae Fructus for primary dysmenorrhea treatment. MATERIALS AND METHODS: The primary dysmenorrhea mouse model was used in this study. Except for the control group and the normal administration group, the mice of other groups were subcutaneously injected with estradiol benzoate (10 mg/kg/d) for 10 consecutive days. From the 5th day of the ten-day model period, the positive control groups were given 0.075 g/kg ibuprofen and 7.5 g/kg Leonurus granule, the drug groups were given 0.2 g/kg, 0.4 g/kg, 0.8 g/kg Akebiae Fructus extract, the normal administration group was given 0.8 g/kg Akebiae Fructus extract, and the same volume saline was given in the control group. On the tenth day, oxytocin (10 U/kg) was peritoneally injected after estradiol benzoate injected 1 h. After the oxytocin injection, writhing behavior was observed for 30 min. Then the uterine tissue was collected to measure the level of PGF2α and PGE2, and for histological analysis and transcriptomics analysis. Meanwhile, plasma and urine samples were collected for metabolomic analysis. RESULTS: Akebiae Fructus inhibited the writhing, decreased the PGF2α level and ameliorated the morphological changes. 32 potential metabolic biomarkers in plasma and 17 in urine were found for primary dysmenorrhea, and after Akebiae Fructus treatment, 25 metabolites in plasma and 14 in urine were restored. These altered metabolites were mainly involved in lipid, amino acid and organic acid metabolism. For the transcriptomic study, a total of 2244 differentially expressed genes (1346 up-regulated and 898 down-regulated) were obtained between the control and model group, and 148 differentially expressed genes (DEGs) were found related with Akebiae Fructus treatment of primary dysmenorrhea. Correlation analysis was carried out based on the transcriptomic and metabolomic data. 5 differentially expressed genes (Plpp3, Sgpp2, Arg1, Adcy8, Ak5) were found related with the enrichment metabolic pathways. The mechanism by which Akebiae Fructus ameliorates primary dysmenorrhea may account for the regulation of the gene expression to control the key enzymes in the sphingolipid metabolism, arginine and proline metabolism, glycerophospholipid metabolism and purine metabolism, inhibiting the abnormal secretion of PGF2α, alleviating the uterine contraction and reducing inflammation and pain. CONCLUSIONS: Akebiae Fructus could effectively alleviate the symptoms of primary dysmenorrhea, regulate metabolic disorders, and control the related gene expression in primary dysmenorrhea. The study may provide clues for further study of Akebiae Fructus treatment on primary dysmenorrhea.

Increased serum asymmetric dimethylarginine levels in primary dysmenorrhea.

BACKGROUND: Primary dysmenorrhea is a common disorder among young women, and uterine ischemia plays an important role in pelvic pain. Asymmetric dimethylarginine (ADMA) is accepted as a strong marker of endothelial dysfunction. OBJECTIVE: To investigate the role of ADMA in primary dysmenorrhea. METHODS: Thirty-three patients with primary dysmenorrhea and 29 healthy controls were evaluated in a hospital outpatient clinic-based study. Secondary causes of dysmenorrhea had been ruled out in each patient. LDL cholesterol, triglycerides measured and body mass index were also calculated. Blood samples for determination of ADMA concentration were drawn on the 3rd day of menses in each woman. Groups were compared for statistically significant difference by Mann-Whitney U test. RESULTS: Groups did not differ in age or hormone levels. ADMA level was higher in women with dysmenorrhea compared to healthy controls (Mann-Whitney U test, Z = -2.24, p = 0.025). ADMA levels showed positive correlation with age and erythrocyte sedimentation rate in the first group (Spearman's rho = 0.360, p = 0.040, and r = 0.379, p = 0.029, respectively). Although erythrocyte sedimentation rate and C-reactive protein (CRP) were positively correlated, no significant correlations were found between high-sensitivity CRP and ADMA level in the first group (Spearman's rho = 0.048, p = 0.749). CONCLUSION: ADMA concentrations are elevated in primary dysmenorrhea compared to healthy controls. This suggests that endothelial dysfunction plays a role in primary dysmenorrhea.

Efficacy of gonadotropin-releasing hormone agonist and an extended-interval dosing regimen in the treatment of patients with adenomyosis and endometriosis.

AIMS: To determine the effects of gonadotropin-releasing hormone agonist (GnRH-a) and an extended-interval dosing regimen in the treatment of patients with adenomyosis and endometriosis. METHODS: This was a prospective observational study in the setting of a hospital outpatient clinic. Seventy women suffering from adenomyosis and endometriosis were randomly divided into 2 groups: extended-interval dosing (experimental group) and conventional dosing (control group). METHODS: Patients in the experimental group received a 4-dose regimen (triptorelin 3.75 mg by intramuscular injection every 6 weeks for a total of 4 doses). The patients in the control group received a conventional regimen (1 injection every 4 weeks for a total of 6 doses). The main outcome measures were relief and recurrence of dysmenorrhea and related climacteric symptoms, reduction of uterine volume, and serum levels of 17-beta-oestradiol (E(2)), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). RESULTS: The reliving rate of dysmenorrhea was 100% in patients treated with both the new regimen and the convention regimen after 6 months. The uterine volume was reduced 37.6% and 39.2%, respectively. And the levels of LH, FSH and E(2) were decreased significantly (p < 0.001). The E(2 )levels were reduced to the postmenopausal level. The hormone profile of the experimental group was similar to that of the control group (p > 0.05). CONCLUSION: The use of the extended-interval dosing regimen of triptorelin depot in patients with adenomyosis or endometriosis results in a consistent hypo-oestrogenised state, which is similar to that achieved by the conventional regimen. The new regimen reduces the cost of treatment.

Low Serum Oxytocin Concentrations Are Associated with Painful Menstruation.

Oxytocin-dependent mechanisms are hypothesized to contribute to painful menses, but clinical trials of oxytocin antagonists for dysmenorrhea have had divergent outcomes. In contrast, broader studies have shown that increased systemic oxytocin concentrations are associated with increased pain tolerance and improved psychosocial function. We sought to confirm whether increased serum oxytocin concentrations are associated with menstrual pain and other psychosocial factors. Women with a history of primary dysmenorrhea (n = 19), secondary dysmenorrhea (n = 12), and healthy controls (n = 15) completed pain and psychosocial questionnaires, provided a medical history, and rated their pain during the first 48 h of menses. Serum samples were collected during menses to measure oxytocin concentrations. Oxytocin was significantly lower in participants with a history of primary (704 ± 33 pg/mL; p < 0.001) or secondary (711 ± 66 pg/mL; p < 0.01) dysmenorrhea compared to healthy controls (967 ± 53 pg/mL). Menstrual pain over the past 3 months (r = -0.58; p < 0.001) and during the study visit (r = -0.45; p = 0.002) was negatively correlated with oxytocin concentrations. Pain catastrophizing (r = -0.39), pain behavior (r = -0.32), and pain interference (r = -0.31) were also negatively correlated with oxytocin levels (p's < 0.05). Oxytocin was not significantly correlated with psychosocial factors. Contrary to our hypothesis, women with a history of primary or secondary dysmenorrhea had lower oxytocin concentrations during menses when compared to healthy controls. Lower circulating oxytocin concentrations were also associated with worse menstrual pain and pain-related behavior. When considering the existing literature, low circulating oxytocin may be a sign of dysfunctional endogenous pain modulation.

The Relationship between Serum Ischemia-Modified Albumin Levels and Uterine Artery Doppler Parameters in Patients with Primary Dysmenorrhea.

OBJECTIVE: Primary dysmenorrhea occurs due to abnormal levels of prostanoids, uterine contractions, and uterine blood flow. However, the reasons for pain in primary dysmenorrhea have not yet been clarified. We examined the blood flow alterations in patients with primary dysmenorrhea and determined the relationship between ischemia-modified albumin (IMA) levels, as an ischemia indicator, and primary dysmenorrhea. METHODS: In the present study, 37 patients who had primary dysmenorrhea and were in their luteal and menstrual phase of their menstrual cycles were included. Thirty individuals who had similar demographic characteristics, who were between 18 and 30 years old and did not have gynecologic disease were included as control individuals. Their uterine artery Doppler indices and serum IMA levels were measured. RESULTS: Menstrual phase plasma IMA levels were significantly higher than luteal phase IMA levels, both in the patient and in the control groups (p < 0.001). Although the menstrual phase IMA levels of patients were significantly higher than those of controls, luteal phase IMA levels were not significantly different between the two groups. Menstrual uterine artery pulsatility index (PI) and resistance index (RI) of primary dysmenorrhea patients were significantly different when compared with luteal uterine artery PI and RI levels. There was a positive correlation between menstrual phase IMA and uterine artery PI and RI in the primary dysmenorrhea. CONCLUSION: Ischemia plays an important role in the etiology of the pain, which is frequently observed in patients with primary dysmenorrhea. Ischemia-modified albumin levels are considered as an efficient marker to determine the severity of pain and to indicate ischemia in primary dysmenorrhea.

Effect of traditional Chinese medicine formula GeGen decoction on primary dysmenorrhea: A randomized controlled trial study.

ETHNOPHARMACOLOGICAL RELEVANCE: GeGen Decoction, a well-known Chinese herbal formula, is widely used in China and other Asian countries to treat gynecological diseases, including primary dysmenorrhea. Pharmacological studies have confirmed that GeGen Decoction is able to inhibit spasmodic contractions of the uterus in vivo and in vitro. AIM OF THE STUDY: The objective of this study is to examine the efficacy and safety of GeGen Decoction on primary dysmenorrheic patients. METHODS: This was a randomized, double-blinded, placebo-controlled trial. GeGen Decoction or placebo was administered a week before the expected start of each cycle for three consecutive menstrual periods. Between-group differences in pain intensity were detected by visual analogue scale (VAS). In addition, serum levels of arginine vasopressin (AVP) and estrogen (E) were examined by enzyme-linked immunosorbent assay. Metabolomic analysis was further used to evaluate the influence of GeGen Decoction on the metabolomics of primary dysmenorrheic patients. RESULTS: A total of 71 primary dysmenorrheic women were recruited and 30 participants met the criteria were randomized into GeGen Decoction or placebo group. After three consecutive menstrual cycles' treatments, the VAS score of the GeGen Decoction group was significantly lower than that of the placebo group. Both serum levels of AVP and E decreased after GeGen Decoction administration, while the placebo seemed to have little effect on either of the index. Moreover, after GeGen Decoction treatment, seven important metabolites were identified by metabolomic analysis compared to the placebo group. No abnormalities in blood biochemical and routine physical examination pre and post GeGen Decoction intervention were observed. CONCLUSIONS: GeGen Decoction can remarkably relieve the severity of menstrual pain without obvious adverse effects. Its therapeutic effect on primary dysmenorrhea might be related to the regulation of pituitary hypothalamic ovarian hormones, and interfering with the metabolic change.

Does aerobic exercise induced-analgesia occur through hormone and inflammatory cytokine-mediated mechanisms in primary dysmenorrhea?

The popular accepted explanation for the pathogenesis of primary dysmenorrhea is elevated levels of uterine prostaglandins. Aetiological studies report that production of prostaglandins is controlled by the sex hormone progesterone, with prostaglandins and progesterone displaying an inverse relationship (i.e. increased progesterone levels reduce prostaglandin levels). Pro-inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-α]) are also implicated in the pathogenesis of primary dysmenorrhea. High-intensity aerobic exercise is effective for decreasing pain quality and intensity in women with primary dysmenorrhea. However, why and how aerobic exercise is effective for treatment of primary dysmenorrhea remain unclear. Our preliminary non-randomized controlled pilot study to examine the effects of high-intensity aerobic exercise on progesterone, prostaglandin metabolite (13,14-dihydro-15-keto-prostaglandin F2 alpha (KDPGF2α), TNF-α, and pain intensity found increases in progesterone and decreases in KDPGF2α, TNF-α, and pain intensity following high-intensity aerobic exercise relative to no exercise. Given these promising preliminary findings, as well as what is known about the pathogenesis of primary dysmenorrhea, we propose the following scientific hypothesis: high-intensity aerobic exercise utilizes hormone (progesterone) and inflammatory cytokine-mediated mechanisms to reduce the pain associated with primary dysmenorrhea.

Reproductive hormones in plasma over the menstrual cycle in primary dysmenorrhea compared with healthy subjects.

The pathogenesis of primary dysmenorrhea is still poorly understood. The objective of the present investigation was to study differences in plasma concentrations of reproductive hormones in women with primary dysmenorrhea vs. healthy controls. In a prospective, parallel-group study we determined the plasma concentrations of oxytocin, vasopressin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17beta-estradiol (17beta-E2), progesterone and prostaglandin F 2alpha metabolite (15-keto-13,14-dihydro-PGF 2alpha) over one menstrual cycle in eight women with primary dysmenorrhea and eight healthy volunteers. In dysmenorrheic women the plasma concentration of oxytocin was significantly higher at menstruation (p = 0.0084) and that of vasopressin significantly lower at ovulation (p = 0.0281) compared with healthy women. They had also higher FSH levels in the early follicular phase (p = 0.0087) and at menstruation (p = 0.0066) and the 17beta-E2 concentration was higher in the late follicular phase (p = 0.0449). No differences were seen for LH, progesterone and PGF 2alpha metabolite. The differences of oxytocin, vasopressin, FSH and 17beta-E2 concentrations found in plasma suggest an involvement of these hormones in mechanisms of primary dysmenorrhea. These mechanisms seem to be mainly regulated through the hypothalamus and pituitary. The influence of oxytocin on the non-pregnant uterus seems to be more important than earlier believed.