Mechanistic Characterization of Uterine Pain (MCUP) to Improve Diagnosis and Treatment for Dysmenorrhea
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 183
- 试验地点
- 1
- 主要终点
- Number of Participants With Concordant Phenotype Assignment at Both MRI Visits
研究概览
简要总结
There are limited treatment options for management of dysmenorrhea, and the physiological processes they affect are not completely understood. For example, NSAIDs are effective in reducing menstrual pain in some women by inhibition of prostaglandin synthesis, but whether those effects are mediated by affecting contractility, perfusion, or hypoxemia is unknown. Understanding how these drugs relieve menstrual pain (and why they fail) would be of substantial clinical significance. Given the foregoing, Two Specific Aims are proposed:
Aim #1: Characterize menstrual pain phenotypes associated with impairments in myometrial activity, perfusion, and/or oxygenation. Continuous MRI scans of the uterus will be performed with simultaneous measurement of self-reported pain in healthy women and those experiencing menstrual pain. The investigators will include cohorts of women with imaging diagnosed leiomyoma and surgically-confirmed endometriosis to evaluate the contribution of structurally identifiable factors. Based on preliminary data, the investigators anticipate finding four phenotypes with menstrual pain related to: 1) myometrial activity, 2) inadequate perfusion and/or oxygenation, 3) a combination of phenotypes 1 & 2, and 4) a non-uterine source.
Aim #2: Evaluate the effects of naproxen on myometrial activity, perfusion, and/or oxygenation with respect to pain relief. In women with primary dysmenorrhea, the investigators will acquire pelvic MRI scans and evaluate self-reported menstrual cramping pain before and after administration of randomized naproxen or placebo.
Naproxen could principally affect one or more potential sources of uterine pain such as myometrial activity, perfusion, and/or oxygenation. The investigators will corroborate preliminary data findings, which suggest menstrual phenotypes with myometrial activity will be more likely to respond. Conversely, Aim 2 will also elucidate the mechanisms responsible for inadequate pain relief from naproxen.
Bioavailability of naproxen levels and other molecules associated with NSAID-resistance will be evaluated from the serum of participants after taking naproxen using HPLC-MS.
详细描述
Due to a lack of noninvasive tools to study uterine physiology, the root causes of menstrual cramping pain within primary dysmenorrhea and secondary dysmenorrhea (leiomyoma, endometriosis, adenomyosis) remain unknown. This pain does not respond to typical over-the-counter anti-inflammatories in 15% of women and is a leading risk factor for developing challenging chronic pelvic pain disorders. In order to guide drug discoveries and create personalized treatment approaches, it is essential to unveil the underlying mechanisms of dysmenorrhea. Our research program has focused on key gaps in our knowledge of uterine physiology, such as the contributions of uterine contractions, perfusion, and oxygenation to menstrual pain. Although these factors are strongly implicated in this debilitating pain disorder, confirmatory human data is still needed. Such research would be quite timely, as numerous drug candidates targeting these potential mechanisms already exist. Our collaborative team has developed MRI-based tools to noninvasively and dynamically measure uterine contractions, perfusion, relative tissue oxygenation, and metabolites indicative of anaerobic respiration. The investigators have also pioneered methods that link spontaneous pain report to simultaneous uterine events. Together, these methods will allow us to evaluate the contribution of contractility, perfusion, or hypoxemia to menstrual pain. Notably, our preliminary data supports our central hypothesis that menstrual pain is associated with different phenotypes involving myometrial hypercontractility, impaired uterine perfusion, uterine hypoxemia, or a non-uterine source. Since understanding how current anti-inflammatory medications relieve or prevent pain (and why they fail) is valuable for the development of improved treatment strategies, the investigators will also investigate the effects of naproxen on uterine physiology in women with menstrual pain. To test our hypothesized contributions of altered uterine muscle activity, perfusion, and oxygenation on pain, The investigators propose: Aim 1: Characterize menstrual pain phenotypes associated with impairments in myometrial activity, perfusion, and/or oxygenation. Continuous MRI sequences of the uterus will be performed with simultaneous measurement of self-reported pain in healthy women and those experiencing menstrual pain. A cohort of women with leiomyoma and endometriosis will also be analyzed to evaluate the contribution of myometrial activity, perfusion, and oxygenation in women with structurally identifiable conditions. Aim 2: Evaluate the effects of naproxen on myometrial activity, perfusion, and/or oxygenation with respect to pain relief. Preliminary data suggests unresolved myometrial activity and inadequate naproxen absorption are associated with insufficient pain relief. Evaluating the naproxen-dependent effects of uterine physiology will provide a foundation for diagnostic tests to indicate relevant personalized treatment for patients that have failed conventional treatments. Further translation of these studies could advance mechanisms for discovery in other chronic pelvic pain conditions and uterine disorders such as idiopathic preterm labor and unexplained infertility.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Inclusion Criteria for Primary Dysmenorrhea Group: All cases (n=70) will have pain in the region between the umbilicus and the perineum, above the level of the inguinal ligament, and rate their average pain greater than or equal to 6/10 (0 = no pain; 10 = worst imaginable pain) during menses when not using NSAIDs. The investigators will use strict inclusion criteria and verification with structural MRI to ensure patients with primary dysmenorrhea most likely do not have endometriosis, leiomyoma, or adenomyosis as described below. It is not possible to reliably evaluate superficial endometriosis with MRI (Nisenblat et al., 2016), but suspicious cases for deep infiltrating endometriosis will be confirmed by the radiologists who routinely evaluate MRIs for our gynecological surgical service. Although it is impossible to rule out endometriosis without surgery, in select cases The investigators will use clinical exams and criteria supported by decision trees (Eskenazi et al., 2001; Chapron et al., 2005, 2011; Vercellini et al., 2007) that suggest the detection of endometriosis stage 2 or higher would be unlikely (<15%) in this population. Participants with dysmenorrhea that rate their bowel pain, dyspareunia, or non-menstrual pelvic pain equal to or greater than 40 on 0-100 visual analog pain scale on the McGill Pain Questionnaire will be given the option to participate in an additional clinical exam visit. To reduce the likelihood of comorbid endometriosis, primary dysmenorrhea participants with symptoms of endometriosis described above, will be required to have a negative clinical exam and no immediate family history of endometriosis to qualify for final analyses.
- •Inclusion Criteria for Leiomyomata Group: The investigators will also study participants with leiomyomata (n=20) because it is a frequent cause of menstrual pain and will often be identified in disqualified primary dysmenorrhea participants. Leiomyomata (nondegenerated) will be diagnosed by foci homogeneously hypointense on T2, but isointense relative to myometrium on T1 according to standard definitions (Kubik-Huch et al., 2018). To reduce variability within this category, the investigators will restrict enrollment to small to medium sized intramural leiomyomata (30 to 150 cm3 combined volume). The investigators anticipate 10 participants with leiomyomata will be identified from incidental MRI during this study, while 10 more will be recruited from advertisements and our clinic. A smaller cohort is studied here because the main purpose of this group is to establish whether the physiological basis for menstrual pain in women with leiomyomata is significantly different than women with primary dysmenorrhea. Participants with leiomyomata, who are also symptomatic with surgically diagnosed endometriosis will be excluded.
- •Inclusion Criteria for Endometriosis Group: Participants without leiomyomata, but symptomatic for endometriosis (n=20) will be enrolled before planned surgical excision (follow-up surgery from an earlier diagnosis). The investigators will confirm a diagnosis of Stage 2, 3, or 4 endometriosis following surgery. For the patients without confirmed abnormal surgical findings for endometriosis with dysmenorrhea will be considered as primary dysmenorrhea cases. Dr. Tu's pelvic pain division performs over 100 laparoscopic pain evaluations annually (many with deep infiltrating disease) enabling us to characterize MRI signals in surgically confirmed endometriosis patients. A smaller cohort is studied here because the main purpose of this group is to establish whether the physiological basis for menstrual pain in women with endometriosis is significantly different than women with primary dysmenorrhea.
- •Inclusion Criteria for Healthy Controls: Healthy control cases (n=20) must rate their average menstrual pain < =2/10 over that past 6 months (without NSAID use) and have no other concurrent pain diagnoses or leiomyomata. Their lack of concurrent pain diagnoses will be confirmed with questionnaires (NIH PROMIS scales, Rome Foundation IBS criteria (Palsson et al., 2016), AUA bladder pain syndrome criteria (Hanno et. al. 2012), and the Complex Medical Symptom Inventory (Williams and Schilling, 2009) and a medical exam screen. Healthy controls and participants with primary dysmenorrhea will be ratio-metrically age-matched with comparable pregnancy history to ensure similar demographics between groups.
排除标准
- •Age restrictions for all study participants: Regularly menstruating women (age 18-45) will be identified using our well-tested community-wide recruitment strategy, including approaching our division's busy gynecological disorders clinic, and the departments of Ob/Gyn at NorthShore and the University of Chicago. Although women above the age of 45 can have menstrual pain, irregularities in perimenopause could cause confounding effects on uterine physiology and scheduling difficulty. Similarly, irregularities in menstruation, ovulation, and pain levels in participants under age 18 could potentially detract from meaningful interpretation of phenotypes (Seidman et al., 2018). Additionally, before age 18, the uterus is still developing and substantially increasing in size (Porcu et al., 1989; Verguts et al., 2013). Thus, to limit potential confounding effects, participants under the age of 18 will be investigated in a separate study.
- •Menstruation-related exclusion criteria for all study participants: The investigators will exclude certain participants with conditions associated with the absence of regular menses such as polycystic ovarian syndrome, pregnancy, current use of any continuous hormonal medication or contraceptive, or Asherman's syndrome.
- •MRI-related or participation related exclusion criteria for all study participants:
- •The investigators will exclude participants with criteria that would affect our ability to obtaining meaningful MRI data such as
- •presence of an intrauterine device (IUD). The use of an IUD potentially affects interpretability of MRI because it creates an imaging artifact in the endometrium extending to the myometrium.
- •inability to read or comprehend the informed consent written in English,
- •history of metallic implants,
- •history of metallic injury,
- •any diagnosed condition that would preclude investigation with MRI (e.g., claustrophobia),
- •allergy or inability to tolerate naproxen
- •Exclusion criteria for known factors that affect the interpretability of the data for all study participants:
- •thyroid dysfunction,
- •adrenal dysfunction,
- •renal disorders,
- •liver disorders,
- •coagulopathy,
- •prolactinoma,
- •von Willebrand disease,
- •platelet disorders,
- •diabetic neuropathy,
- •gastrointestinal conditions or surgeries that would affect naproxen absorption,
- •active genitourinary or sexually transmitted infection
- •Provisional exclusion for primary analyses for all study participants: Acute or chronic conditions associated with pelvic pain with a defined anatomical cause other than endometriosis or leiomyoma (e.g., pathological ovarian cysts, significant persistent hydro/hematosalpinx, untreated pelvic inflammatory disease, active pelvic or abdominal malignancies, Mullerian anomalies, or stage 3 uterine prolapse), and comorbid diagnosis of significant leiomyoma and endometriosis.
- •Note: these exclusion criteria may be incidentally discovered after the MRI scan and confirmed with a radiologist's or Dr. Tu's diagnosis.
- •Provisional exclusion for adenomyosis group: Because the frequency of adenomyosis is low or unknown, and may consist of multiple subtypes resulting in heterogeneity and inadequate statistical power, adenomyosis patients are not a planned study group and diagnosed cases will be initially excluded from recruitment. Focal and diffuse adenomyosis will be excluded by guidelines (Chapron et al., 2017) adapted from the Kishi criteria (Kishi et al., 2012): maximal junctional zone thickness exceeding 12 mm, a ratio of junctional zone thickness to myometrium exceeding 40%, or high-intensity foci within the myometrium. If a substantial number of adenomyosis participants participate, as discovered after-the-fact with MRI, results will be analyzed.
- •Intermediate levels of dysmenorrhea pain exclusion: Participants with mild menstrual pain (between 3 and 5 on a 0-10 scale) will be excluded. Our prior experience with this cohort (Westling et al., 2013) suggests that The investigators may encounter a floor effect when studying the effectiveness of NSAIDs. Also, since this cohort is most likely to respond to NSAIDs, it is imperative The investigators study the mechanisms of the most severe sufferers of refractory menstrual pain.
研究组 & 干预措施
Naproxen First, Then Placebo
Participants randomized to this sequence take a single oral 550 mg naproxen sodium tablet at the first menstrual MRI visit and a matching placebo pill at the second MRI visit (a subsequent menstrual episode, 1-2 months later). At each visit the pill is taken immediately after the pre-treatment scan, approximately 90 minutes before the post-treatment scan. Allocation is quadruple-masked: assignment was randomized in REDCap using a block size known only to the study statistician, with naproxen and identical-appearing placebo dispensed in coded containers by the clinical research pharmacy.
干预措施: Placebo (Drug)
Placebo First, Then Naproxen
Participants randomized to this sequence take a matching placebo pill at the first menstrual MRI visit and a single oral 550 mg naproxen sodium tablet at the second MRI visit (a subsequent menstrual episode, 1-2 months later). Pill timing relative to the scans, blinding, randomization, and pharmacy dispensing are identical to the other sequence.
干预措施: Placebo (Drug)
Naproxen First, Then Placebo
Participants randomized to this sequence take a single oral 550 mg naproxen sodium tablet at the first menstrual MRI visit and a matching placebo pill at the second MRI visit (a subsequent menstrual episode, 1-2 months later). At each visit the pill is taken immediately after the pre-treatment scan, approximately 90 minutes before the post-treatment scan. Allocation is quadruple-masked: assignment was randomized in REDCap using a block size known only to the study statistician, with naproxen and identical-appearing placebo dispensed in coded containers by the clinical research pharmacy.
干预措施: Naproxen Sodium (Drug)
Placebo First, Then Naproxen
Participants randomized to this sequence take a matching placebo pill at the first menstrual MRI visit and a single oral 550 mg naproxen sodium tablet at the second MRI visit (a subsequent menstrual episode, 1-2 months later). Pill timing relative to the scans, blinding, randomization, and pharmacy dispensing are identical to the other sequence.
干预措施: Naproxen Sodium (Drug)
结局指标
主要结局
Number of Participants With Concordant Phenotype Assignment at Both MRI Visits
时间窗: Two menstrual MRI visits separated by 1 to 2 menstrual cycles (approximately 4 to 8 weeks).
Menstrual pain phenotypes were derived post hoc rather than assigned. Eleven quantitative signal variables extracted from HASTE and BOLD sequences of the pre-dose menstrual MRI scan were reduced by principal component analysis (6 components retained), and scans were grouped by Ward hierarchical clustering, which yielded three reproducible phenotypes. Each participant's two menstrual MRI scans were independently assigned to one of these phenotypes. A participant was counted as concordant if both scans were assigned to the same phenotype. Reported as the number and percentage of participants with concordant assignment.
Frequency of Uterine Contractions and BOLD Oxygenation-desaturation Events by Menstrual Pain Phenotype
时间窗: Pre-dose menstrual MRI scan at each MRI visit; each scan approximately 1 hour.
Menstrual pain phenotypes were derived post hoc rather than assigned. Eleven quantitative signal variables extracted from HASTE and BOLD sequences of the pre-dose menstrual MRI scan were reduced by principal component analysis (6 components retained), and scans were grouped by Ward hierarchical clustering, which yielded three reproducible phenotypes. Clustering was performed at the scan level; each participant contributed up to two scans (84 participants, 119 scans). This measure reports the mean number of uterine contractions and BOLD oxygenation-desaturation events detected per 10-minute scan within each phenotype. R2\* and arterial spin labeling sequences were not acquired in this round and were not included in phenotyping.
Mean Duration of Individual Uterine Contractions by Menstrual Pain Phenotype
时间窗: Pre-dose menstrual MRI scan at each MRI visit; each scan approximately 1 hour.
Menstrual pain phenotypes were derived post hoc rather than assigned. Eleven quantitative signal variables extracted from HASTE and BOLD sequences of the pre-dose menstrual MRI scan were reduced by principal component analysis (6 components retained), and scans were grouped by Ward hierarchical clustering, which yielded three reproducible phenotypes. Clustering was performed at the scan level; each participant contributed up to two scans (84 participants, 119 scans). This measure reports the mean duration of an individual uterine contraction within each phenotype. Duration was quantified as the number of HASTE frames spanning each contraction, acquired at 2 frames per second, and is reported here in seconds. Longer values indicate contractions of greater individual duration.
Myometrial and Junctional Zone Thickness by Menstrual Pain Phenotype
时间窗: Pre-dose menstrual MRI scan at each MRI visit; each scan approximately 1 hour.
Menstrual pain phenotypes were derived post hoc rather than assigned. Eleven quantitative signal variables extracted from HASTE and BOLD sequences of the pre-dose menstrual MRI scan were reduced by principal component analysis (6 components retained), and scans were grouped by Ward hierarchical clustering, which yielded three reproducible phenotypes. Clustering was performed at the scan level; each participant contributed up to two scans (84 participants, 119 scans). This measure reports mean myometrial and junctional zone thickness, measured in millimetres at the anterior and posterior uterine wall, within each phenotype.
BOLD Signal Intensity and Desaturation Dip Magnitude by Menstrual Pain Phenotype
时间窗: Pre-dose menstrual MRI scan at each MRI visit; each scan approximately 1 hour.
Phenotypes were derived post hoc by principal component analysis and Ward hierarchical clustering of eleven HASTE and BOLD signal variables from the pre-dose menstrual MRI scan, at the scan level; each participant contributed up to two scans (84 participants, 119 scans). A desaturation event is a transient drop in BOLD signal. Baseline signal intensity is the mean BOLD signal preceding a desaturation event; minimum signal intensity is the mean signal at the nadir of the event; range of signal change is the difference between them. Higher baseline and minimum values indicate greater BOLD signal, and a larger range indicates a deeper desaturation, i.e. a greater transient drop in oxygenation. Scans with no desaturation event were assigned a nadir equal to baseline and a range of zero. Values are in arbitrary scanner signal intensity units and are not comparable across studies.
Percentage Change in BOLD Signal From Baseline by Menstrual Pain Phenotype
时间窗: Pre-dose menstrual MRI scan at each MRI visit; each scan approximately 1 hour.
Menstrual pain phenotypes were derived post hoc rather than assigned. Eleven quantitative signal variables extracted from HASTE and BOLD sequences of the pre-dose menstrual MRI scan were reduced by principal component analysis (6 components retained), and scans were grouped by Ward hierarchical clustering, which yielded three reproducible phenotypes. Clustering was performed at the scan level; each participant contributed up to two scans (84 participants, 119 scans). Percentage signal change expresses the magnitude of the BOLD desaturation as a proportion of baseline signal intensity, so larger values indicate a deeper transient drop in oxygenation. It is defined only where a desaturation event was detected; scans without a detected event were assigned a value of zero. Phenotype P2 was characterized by near-absent BOLD activity, so its distribution consists predominantly of these structural zeros.
Change in Junctional Zone Thickness From Pre-dose to Post-dose Scan, Naproxen Versus Placebo
时间窗: Pre-dose scan to post-dose scan at each of two menstrual MRI visits; the post-dose scan began approximately 90 minutes after dosing (each scan approximately 1 hour).
Within-subject change in junctional zone thickness, measured in millimetres, from the pre-dose to the post-dose scan, compared between the naproxen and placebo conditions in participants with primary dysmenorrhea. Change is calculated as post-dose minus pre-dose, so positive values indicate greater thickness after dosing. Each participant contributed a change score under both conditions. Row numbers analyzed differ because not every participant had both scans measurable at both wall locations. Post-dose BOLD sequences were successfully acquired at only 5 of 39 crossover visit pairs, and R2\* and arterial spin labeling sequences were not acquired in this round, so no naproxen-versus-placebo comparison is reported for those signal families.
Change in Uterine Contraction Frequency From Pre-dose to Post-dose Scan, Naproxen Versus Placebo
时间窗: Pre-dose scan to post-dose scan at each of two menstrual MRI visits; the post-dose scan began approximately 90 minutes after dosing (each scan approximately 1 hour).
Within-subject change in the number of uterine contractions detected per 10-minute scan, from the pre-dose to the post-dose scan, compared between the naproxen and placebo conditions in participants with primary dysmenorrhea. Change is calculated as post-dose minus pre-dose, so positive values indicate more contractions after dosing. Each participant contributed a change score under both conditions. Post-dose BOLD sequences were successfully acquired at only 5 of 39 crossover visit pairs, and R2\* and arterial spin labeling sequences were not acquired in this round, so no naproxen-versus-placebo comparison is reported for those signal families.
次要结局
- Agreement Between Primary and Sensitivity Phenotype Clustering Solutions (Adjusted Rand Index)(Two menstrual MRI visits separated by 1 to 2 menstrual cycles (approximately 4 to 8 weeks). Pre-dose scan at each visit assessed.)
- Correlation of NSAID Resistance With Clinical/Psychosocial Covariates(Peak pre-dose pain to 6 hours after naproxen dosing at the naproxen menstrual MRI visit.)
- Correlation of NSAID Resistance With Serum Naproxen (90 Min)(Peak pre-dose pain to 6 hours after naproxen dosing at the naproxen menstrual MRI visit; serum was sampled 90 minutes after dosing.)
研究者
Kevin Hellman
Research Associate Professor
Endeavor Health