Pathophysiology Of Primary Dysmenorrhea Research Articles

A Narrative Review on the etiopathogenesis of Primary Dysmenorrhea with reference to Kastartava in Ayurveda literature

Objectives: Different dimensions of Primary Dysmenorrhea in Ayurveda literature has been explored and conceptualised it with the available physiological and anatomical understanding. Content: The concept of Primary Dysmenorrhea is better understood upon the basic understanding of Kastartava dating back to the phase of adolescence. 75% of adolescent girls’ experiences problems related to menstruation including delayed, irregular, painful, and heavy menstrual bleeding. Among these, painful menstruation or dysmenorrhea is the most common gynecological problem seen in reproductive age group. “Primary dysmenorrhea, one among its two types, is a cyclical lower abdominal or pelvic pain of sufficient magnitude so as to incapacitate day to day activities without any identifiable or evident pelvic pathology”. Ayurveda classics were reviewed to analyse the various aspects of Kastartava and correlated with research papers in terms of evidence-based physiological and anatomical advancements. Databases like PubMed, Scopus were searched using keywords like Shoola, Kastartava, Udavartini, Vatiki Yonivyapat, Dysmenorrhea, Primary Dysmenorrhea AND Ayurveda, Pain measurement, Quality of life, Inflammatory Markers, Prostaglandin theory. Summary: Various aspects of Shoola and Kastartava in Ayurveda from evidence-based advancements in Primary Dysmenorrhea based on recent researches have been put forward for basic evidence in relation with Pathophysiology of Primary Dysmenorrhea. Outlook: Understanding the pathophysiology of pain in Primary Dysmenorrhea with respect to the clinical presentation of Kastartava will give new insights to manage the clinical condition.

Uncovering the effects and mechanism of Danggui Shaoyao San intervention on primary dysmenorrhea by serum metabolomics approach

Danggui Shaoyao San (DSS) is a well-known prescription for relieving primary dysmenorrhea (PD) of women in China. However, its pharmacological mechanism has not been thoroughly uncovered. Here, an integrative UPLC-Q-TOF-MS-based serum metabolomics approach coupled with multivariate data analysis has been proposed to investigate the effects and mechanism of DSS on estradiol benzoate and oxytocin-induced PD rats. 31 potential biomarkers of PD were screened and identified, mainly involving phenylalanine, tyrosine and tryptophan biosynthesis, glycerophospholipid metabolism, primary bile acid biosynthesis, and the occurrence of PD could destroy biological homeostasis in vivo by monitoring these pathways. After DSS treatment, 18 identified different metabolites were restored to the nomal state in varying degrees and could be potential biomarkers contributing to the treatment of DSS. These findings implyed that DSS exhibited a therapeutic effect on PD rats through regulating multiple abnormal pathways. Of note, this study discovered some potential biomarkers related to PD for the first time, such as L-tyrosine, glycocholic acid, citric acid, palmitoylcarnitine, cholesterol. It preliminarily proved the pathophysiology of PD and action mechanisms of DSS on PD, and provided a novel insight into the effectiveness of DSS on PD.

Primary Dysmenorrhea in Relation to Oxidative Stress and Antioxidant Status: A Systematic Review of Case-Control Studies.

Primary dysmenorrhea is defined as painful menstrual cramps of uterine origin in the absence of pelvic pathology and is the most common gynecological disorder among women of reproductive age. The aim of this study was to systematically review case-control studies that have investigated the oxidative stress, antioxidant status, and inflammation markers among women with primary dysmenorrhea and controls. The study protocol was registered with PROSPERO (no. CRD42020183104). By searching PubMed and Scopus databases as well as reference lists, six case-control studies with fifteen eligible markers (seven oxidative stress, seven antioxidant status, one inflammation) were included in this review. The quality of the included studies was assessed as medium or high. The systematic review included 175 women with primary dysmenorrhea and 161 controls. The results indicate an elevated level of oxidative stress, especially of lipid peroxidation among dysmenorrheal women. For the antioxidant status, limited evidence was found for a lower status among primary dysmenorrhea women, and only one study examined one inflammation marker (hs-CRP), which makes it impossible for such a conclusion. To establish whether oxidative stress, antioxidant status or inflammation participate in the pathophysiology of primary dysmenorrhea, high-quality studies with larger study groups and clear case definitions are needed.

Primary Dysmenorrhea: Diagnosis and Therapy.

Primary dysmenorrhea is defined as pain during the menstrual cycle in the absence of an identifiable cause. It is one of the most common causes of pelvic pain in women. Dysmenorrhea can negatively affect a woman's quality of life and interfere with daily activities. The pathophysiology of primary dysmenorrhea is likely a result of the cyclooxygenase pathway producing increased prostanoids, particularly prostaglandins (PGs). The increased PGs cause uterine contractions that restrict blood flow and lead to the production of anaerobic metabolites that stimulate pain receptors. Women with a history typical for primary dysmenorrhea can initiate empiric treatment without additional testing. Shared decision making is key to effective management of dysmenorrhea to maximize patient compliance and satisfaction. After a discussion of their risks and benefits, extremely effective empiric therapies are nonsteroidal antiinflammatory drugs and contraceptive hormonal therapy. Other treatments for primary dysmenorrhea can be employed solely or in combination with other modalities, but the literature supporting their use is not as convincing. The physician should initiate an evaluation for secondary dysmenorrhea if the patient does not report improved symptomatology after being compliant with their medical regimen.

Correlation Between Thalamus-Related Functional Connectivity and Serum BDNF Levels During the Periovulatory Phase of Primary Dysmenorrhea.

The thalamus is a key region for the transmission of nociceptive information in the central modulation of pain and has been studied in the setting of numerous chronic pain conditions. Brain-derived neurotrophic factor (BDNF) is considered an important modulator for mediating nociceptive pathways in chronic pain. The present study aimed to investigate whether there was thalamus-related abnormal functional connectivity or relevant serum BDNF level alterations during periovulation in long-term primary dysmenorrhea (PDM). Thalamic subregions were defined according to the Human Brainnetome Atlas. Functional connectivity analyses were performed in 36 patients in the periovulatory phase and 29 age-, education-, and gender-matched healthy controls. Serum BDNF levels were evaluated by enzyme-linked immunosorbent assay and a significantly higher BDNF level was detected in PDM patients. Compared with HCs, PDM patients had abnormal functional connectivity of thalamic-subregions, mainly involving with prefrontal cortex, sensorimotor cortex, and temporal cortex. In addition, the functional connectivity of thalamic-subregions showed significant interactive effect correlated with serum BDNF level between PDM and HCs. It has been suggested that there were maladaptive or adoptive alteration associated with chronic menstrual pain even without the ongoing menstrual pain. BDNF might play a role in the development and chronicity of central nervous system dysfunction. These findings provided more accurate information about the involvement of the thalamus in the pathophysiology of PDM.

Intergrated metabonomic study of the effects of Guizhi Fuling capsule intervention on primary dysmenorrheal using RP‐UPLC–MS complementary with HILIC‐UPLC–MS technique

Guizhi Fuling capsule (GFC), developed from the traditional Chinese prescription of Guizhi Fuling Wan, has been commonly used for the treatment of primary dysmenorrhea (PD). However, the intervention effective mechanism in vivo has not been well elucidated. In this study, an integrated plasma metabonomic strategy based on RP-UPLC-MS coupled with HILIC-UPLC-MS technique has been developed to investigate the global therapeutic effects and intervention mechanisms of GFC on dysmenorrhea rats induced by oxytocin. The 20 potential biomarkers were identified and primarily related to sphingolipid metabolism, steroid hormone biosynthesis, glycerophospholipid metabolism, amino acid metabolism, lipid metabolism and energy metabolism. The results showed that the GFC has therapeutic effects on rats with dysmenorrhea via the regulation of multiple metabolic pathways. Some new potential biomarkers associated with primary dysmenorrhea such as phenylalanine, tryptophan, taurine, carnitine, betaine, creatine and creatinine have been discovered in this study for the first time. This study provides a metabonomic platform based on RP-UPLC-MS complementary to HILIC-UPLC-MS technique to investigate both nonpolar and polar compounds, so as to get a more comprehensive metabolite information to yield insight into the pathophysiology of PD and assessing the efficacy of GFC on PD rats.

Considerations on pathophysiology of primary dysmenorrhea under the light of alterations in complete blood count parameters

The present study strives to evaluate how the components of complete blood count are altered in women with primary dysmenorrhea. This is a cross-sectional analysis of 155 women with primary dysmenorrhea and 155 women without dysmenorrhea. The primary dysmenorrhea and control groups were matched with respect to age and body mass index. When compared with the controls, the women with primary dysmenorrhea had a significantly younger menarche age, longer menstrual duration, higher leukocyte counts, higher neutrophil counts, and elevated MPV values (p=0.010, p=0.022, p=0.014, p=0.011 and p=0.04 respectively). The logistic regression analysis demonstrated that women with primary dysmenorrhea were more likely to have a younger menarche age (OR=2.14, 95% CI=0.971-3.346, p=0.018), longer menstrual duration (OR=1.91, 95% CI=0.988-2.308, p=0.044), higher leukocyte counts (OR= 2.90, 95% CI=1.040-3.788, p=0.007), and elevated MPV values (OR=3.17, 95% CI=2.056-9.128, p=0.001). The sensitivity and specificity of this model were 84.6% and 77.3%, respectively. Leukocytosis and increased MPV are might be associated with the inflammatory and vasoconstrictory pathogenesis of primary dysmenorrhea, but this result should be confirmed in the future researches.

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.

Transvaginal color Doppler study of uterine blood flow in primary dysmenorrhea.

The pain in primary dysmenorrhea is caused by excessive prostaglandin production that leads to vasoconstriction and uterine ischemia. Changes in uterine blood flow are important factors in pathophysiology of primary dysmenorrhea. The aim of the study was to determine if vasoconstriction of the uterine vessels in patients with primary dysmenorrhea is detectable by transvaginal color Doppler ultrasound. Forty-two women with primary dysmenorrhea and fifty healthy controls were included in this prospective study. Women were examined with transvaginal color Doppler ultrasound on first day of the cycle, once in the follicular and once in the luteal phase. Measurements of pulsatility index in uterine, arcuate, radial and spiral arteries were performed. Student's t-test was used to establish statistical significance between groups. Women in dysmenorrhea group had significantly higher uterine blood flow indices than healthy controls in all three measurements periods. This includes all vessels studied on the first day of the cycle, the radial and spiral arteries during the follicular phase and the arcuate, radial and spiral arteries during the luteal phase. We found that women with primary dysmenorrhea have elevated Doppler indices in uterine arteries not only on first day of the cycle but throughout the whole cycle. Therefore we postulated that primary dysmenorrhea is not only the disorder of menstruation but also a disease of a menstrual cycle as a whole.

Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: a randomized controlled trial

Objective: To determine whether rofecoxib is effective for treating primary dysmenorrhea and whether cyclooxygenase-2 is involved in the pathophysiology of primary dysmenorrhea. Methods: A double-masked, randomized, placebo and active-comparator–controlled clinical trial including 127 subjects with histories of primary dysmenorrhea was conducted in an outpatient clinical research center. Subjects were randomly assigned to placebo, rofecoxib 25 or 50 mg followed by 25 mg every 24 hours as needed, or naproxen sodium 550 mg every 12 hours as needed for up to 3 days. Subjects took all four treatments in a balanced, complete-block, crossover design. Measurements included self-administered questionnaires of analgesic efficacy, spontaneous reports of adverse experiences, physical examinations, and laboratory safety tests. Results: Rofecoxib 25 and 50 mg provided analgesic efficacy greater than placebo ( P ≤ .006) for the primary endpoint of total pain relief over the first 8 hours. For other efficacy endpoints (sum of the pain intensity difference over the first 8 hours, subject’s global evaluation, peak pain relief, peak pain intensity difference, and time to remedication) both doses of rofecoxib were better than placebo ( P ≤ .006) and were not distinguishable from naproxen sodium for all efficacy endpoints. All treatments were well tolerated. Conclusion: Rofecoxib effectively treated primary dysmenorrhea, and cyclooxygenase-2–derived prostanoids play a role in the pathophysiology of primary dysmenorrhea.

Nonsteroidal anti-inflammatory drugs and changing attitudes toward dysmenorrhea

Dysmenorrhea, which may be primary or secondary, is the occurrence of painful uterine cramps during menstruation. Until a decade ago, medical and social attitudes toward dysmenorrhea were shrouded with folklore, psychoanalytical profiles, or psychosomatic bases. In secondary dysmenorrhea, there is a visible pelvic lesion to account for the pain, whereas only a biochemical abnormality is responsible for primary dysmenorrhea. Recent advances in the biochemistry of prostaglandins and their role in the pathophysiology of primary dysmenorrhea and intrauterine device (IUD)-induced dysmenorrhea have now firmly established a rational basis for the disorder. In primary dysmenorrhea, menstrual prostaglandin release is significantly increased but can be readily suppressed to normal levels when nonsteroidal anti-inflammatory drugs (NSAIDs) capable of inhibiting cyclo-oxygenase are given during menstruation. Many clinical trials (controlled and uncontrolled) have demonstrated the efficacy of NSAIDs such as the fenamates, indole-acetic acid derivatives, and arylpropionic acid derivatives in relieving primary dysmenorrhea as well as IUD-induced dysmenorrhea that is also due to elevated prostaglandin levels. With a few of these NSAIDs, it has been shown that the relief of pain is associated with a significant decrease in menstrual fluid prostaglandin levels. Cumulative data of clinical trials indicate that with the effective NSAIDs, 80 percent of patients with significant primary dysmenorrhea can be adequately relieved. Ongoing studies suggest that in some women, endometrial leukotriene, but not PGF 2a production, is increased. With the official approval and availability of several effective NSAIDs for the specific treatment of primary dysmenorrhea in the United States, women who have primary dysmenorrhea have been greatly relieved and their productivity increased. Primary dysmenorrhea affects 50 percent of postpubescent women and absenteeism among the severe dysmenorrheics has been estimated to cause about 600 million lost working hours or 2 billion dollars annually. Thus, an effective, simple, and safe treatment of primary dysmenorrhea for two to three days during menstruation will not only have a positive economic impact but will also enhance the quality of life. The availability of effective dysmenorrhea therapy with NSAIDs has induced greater expectations of relief by the patient, as well as greater willingness to seek medical help, a more rational approach to patient management by physicians, changes in attitude toward women with primary dysmenorrhea, and the debunking of myths about dysmenorrhea that often have been perpetuated as fact. NSAIDs have undoubtedly revolutionized a painful disorder.