Menstrual Cycle Variation in MRI-Based Quantification of Intraluminal Gas in Women With and Without Dysmenorrhea.

Women frequently report increased bloating, flatulence, and pain during the perimenstrual period. However, it is unknown whether women have more intraluminal gas during menses. To evaluate whether pain-free women or women with dysmenorrhea have different amounts of intraluminal bowel gas during the menses, we utilized magnetic resonance imaging (MRI) to determine colonic gas volumes throughout the menstrual cycle. To avoid dietary influence, the participants were instructed to avoid gas-producing foods before their scheduled MRI. We verified the measurement repeatability across the reviewers and obtained an intraclass correlation coefficient of 0.92. There were no significant differences in intraluminal gas volume between menses and non-menses scans (p = 0.679). Even among the women with dysmenorrhea, there was no significant difference in the intraluminal gas volume between menses and non-menses (p = 0.753). During menstruation, the participants with dysmenorrhea had less intraluminal gas than participants without dysmenorrhea (p = 0.044). However, the correlation between the bowel gas volume and the pain symptoms were not significant (p > 0.05). Although increased bowel symptoms and bloating are reported in the women with dysmenorrhea during menses, our results do not support the hypothesis that increased intraluminal gas is a contributing factor. Although dietary treatment has been shown in other studies to improve menstrual pain, the mechanism responsible for abdominal symptoms requires further investigation. Our findings demonstrate that the intraluminal bowel gas volume measurements are feasible and are unaffected by menses under a controlled diet. The method described might prove helpful in future mechanistic studies in clarifying the role of intraluminal bowel gas in other conditions.

Circulating sex steroids and bladder pain sensitivity in dysmenorrhea.

Although elevated estradiol levels facilitate chronic pelvic pain in animal models, it remains to be determined whether sex steroid levels are altered in a cross-section of women with chronic pelvic pain (CPP) and those at-risk for developing CPP. We sought to determine if sex steroid levels are increased in women with menstrual pain and whether those changes were more extreme in two groups of women with worsened pelvic pain profiles: a) dysmenorrhea plus evidence of bladder pain sensitivity and b) bladder pain syndrome. Serum samples were collected during the mid-luteal phase to measure estradiol, progesterone, testosterone, and sex hormone-binding globulin. We also compared quantitative sensory testing profiles to evaluate how sex steroid differences influence proposed pain sensitivity mechanisms. Women with combined dysmenorrhea and bladder sensitivity had higher estradiol concentrations than controls (487 [IQR 390 - 641] vs 404 [336 - 467] pmol/L, p = 0.042). Bladder pain syndrome participants had greater sex hormone-binding globulin than controls (83 [71 - 108] vs 55 [42 - 76 nmol/L; p = 0.027). Levels of pain sensitivity and mood were different across the groups, but the only significant relationship to sex steroids was that sex hormone-binding globulin was correlated to somatic symptoms (r = 0.26, p = 0.03). These findings show women potentially at-risk for CPP and women with diagnosed CPP exhibit altered circulating levels of sex steroids. Because these hormonal differences appear to be independent of mood or pain sensitivity, the role of sex steroids in the emergence of CPP may be via sensitization of visceral afferents.

Development and validation of a real-time method characterizing spontaneous pain in women with dysmenorrhea.

AIM: Prior research has primarily focused on static pain assessment, largely ignoring the dynamic nature of pain over time. We used a novel assessment tool for characterizing pain duration, frequency, and amplitude in women with dysmenorrhea and evaluated how these metrics were affected by naproxen treatment. METHODS: Dysmenorrheic women (n = 25) rated their menstrual pain by squeezing a pressure bulb proportional to the magnitude of their pain. To evaluate whether bulb squeezing was affected by naproxen, we compared parameters before and after naproxen. We also analyzed the correlation between pain relief on a numerical rating scale to changes in bulb squeezing parameters. Random bulb-squeezing activity in pain-free participants (n = 14) was used as a control for nonspecific effects or bias. RESULTS: In dysmenorrheic women, naproxen reduced the duration of the squeezing during a painful bout, the number of painful bouts and bout intensity. Before naproxen, the correlation between these bulb squeeze parameters and self-reported pain on numeric rating scale was not significant (R2 = 0.12, p = 0.304); however, there was a significant correlation between changes in bulb squeeze activity and self-reported pain relief after naproxen (R2 = 0.55, p < 0.001). CONCLUSION: Our study demonstrates a convenient technique for continuous pain assessment, capturing three different dimensions: duration, frequency, and magnitude. Naproxen may act by reducing the duration and frequency of episodic pain in addition to reducing the severity. After further validation, these methods could be used for other pain conditions for deeper phenotyping and assessing novel treatments.

Low Serum Naproxen Concentrations Are Associated with Minimal Pain Relief: A Preliminary Study in Women with Dysmenorrhea.

OBJECTIVE: Incomplete pain relief after administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is common, but it is unknown whether malabsorption or heightened metabolism contributes to NSAID resistance. To explain the etiology of NSAID resistance, we evaluated naproxen absorption and metabolism in relation to pain relief in a pilot study of women with dysmenorrhea. METHODS: During menses, participants completed before and after naproxen ingestion pain assessments. Analgesic effectiveness was calculated as a percent change in pain rating before and after naproxen administration. To evaluate the impact of malabsorption, the correlation between analgesic effectiveness and serum naproxen was analyzed. To identify whether hypermetabolism contributes to NSAID resistance, we also analyzed the metabolite O-desmethylnaproxen. RESULTS: Serum naproxen and O-desmethylnaproxen concentrations of the dysmenorrheic cohort (N = 23, 126 ± 10 µg/mL, 381 ± 56 ng/mL) and healthy controls (N = 12, 135 ± 8 µg/mL, 355 ± 58 ng/mL) were not significantly different (P > 0.05), suggesting that menstrual pain does not affect drug absorption and metabolism. However, nine dysmenorrhea participants had levels of analgesic effectiveness <30%. Among dysmenorrheic women, analgesic effectiveness was correlated with serum naproxen (r = 0.49, P = 0.019) and O-desmethylnaproxen (r = 0.45, P = 0.032) concentrations. After controlling for other gynecological diagnoses, a multivariate model analysis confirmed that lower serum naproxen concentrations were associated with reduced pain relief (P = 0.038). CONCLUSIONS: Our preliminary findings suggest that poor drug absorption contributes to ineffective pain relief in dysmenorrheic women. Future studies should explore whether malabsorption contributes to NSAID resistance for other pain conditions.

Dysmenorrhea subtypes exhibit differential quantitative sensory assessment profiles.

Women who develop bladder pain syndrome (BPS), irritable bowel syndrome, or dyspareunia frequently have an antecedent history of dysmenorrhea. Despite the high prevalence of menstrual pain, its role in chronic pelvic pain emergence remains understudied. We systematically characterized bladder, body, and vaginal mechanical sensitivity with quantitative sensory testing in women with dysmenorrhea (DYS, n = 147), healthy controls (HCs) (n = 37), and women with BPS (n = 25). Previously, we have shown that a noninvasive, bladder-filling task identified a subset of women with both dysmenorrhea and silent bladder pain hypersensitivity, and we repeated this to subtype dysmenorrhea sufferers in this study (DYSB; n = 49). DYS, DYSB, and BPS participants had lower vaginal mechanical thresholds and reported more pain to a cold stimulus during a conditioned pain modulation task and greater pelvic examination after-pain than HCs (P's < 0.05). DYSB participants also had reduced body mechanical thresholds and less conditioned pain modulation compared to HCs and DYS participants (P's < 0.05). Comparing quantitative sensory testing results among the DYS and HC groups only, provoked bladder pain was the only significant predictor of self-reported menstrual pain (r = 0.26), bladder pain (r = 0.57), dyspareunia (r = 0.39), and bowel pain (r = 0.45). Our findings of widespread sensory sensitivity in women with dysmenorrhea and provoked bladder pain, much like that observed in chronic pain, suggest a need to study the trajectory of altered mechanisms of pain processing in preclinical silent visceral pain phenotypes to understand which features convey inexorable vs modifiable risk.

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.

Persistent autonomic dysfunction and bladder sensitivity in primary dysmenorrhea.

Menstrual pain, also known as dysmenorrhea, is a leading risk factor for bladder pain syndrome (BPS). A better understanding of the mechanisms that predispose dysmenorrheic women to BPS is needed to develop prophylactic strategies. Abnormal autonomic regulation, a key factor implicated in BPS and chronic pain, has not been adequately characterized in women with dysmenorrhea. Thus, we examined heart rate variability (HRV) in healthy (n = 34), dysmenorrheic (n = 103), and BPS participants (n = 23) in their luteal phase across a bladder-filling task. Both dysmenorrheic and BPS participants reported increased bladder pain sensitivity when compared to controls (p's < 0.001). Similarly, dysmenorrheic and BPS participants had increased heart rate (p's < 0.01), increased diastolic blood pressure (p's < 0.01), and reduced HRV (p's < 0.05) when compared to controls. Dysmenorrheic participants also exhibited little change in heart rate between maximum bladder capacity and after micturition when compared to controls (p = 0.013). Our findings demonstrate menstrual pain's association with abnormal autonomic activity and bladder sensitivity, even two weeks after menses. Our findings of autonomic dysfunction in both early episodic and chronic visceral pain states points to an urgent need to elucidate the development of such imbalance, perhaps beginning in adolescence.

Abdominal skeletal muscle activity precedes spontaneous menstrual cramping pain in primary dysmenorrhea.

BACKGROUND: Dysmenorrhea is a pervasive pain condition that affects 20-50% of reproductive-aged women. Distension of a visceral organ, such as the uterus, could elicit a visceromotor reflex, resulting in involuntary skeletal muscle activity and referred pain. Although referred abdominal pain mechanisms can contribute to visceral pain, the role of abdominal muscle activity has not yet been investigated within the context of menstrual pain. OBJECTIVE: The goal of this study was to determine whether involuntary abdominal muscle activity precedes spontaneous episodes of menstrual cramping pain in dysmenorrheic women and whether naproxen administration affects abdominal muscle activity. STUDY DESIGN: Abdominal electromyography activity was recorded from women with severe dysmenorrhea (n = 38) and healthy controls (n = 10) during menses. Simultaneously, pain was measured in real time using a squeeze bulb or visual analog rheostat. Ninety minutes after naproxen administration, abdominal electromyography activity and menstrual pain were reassessed. As an additional control, women were also recorded off menses, and data were analyzed in relation to random bulb squeezes. Because it is unknown whether mechanisms of menstrual cramps are different in primary or secondary dysmenorrhea/chronic pelvic pain, the relationship between medical history and abdominal muscle activity was examined. To further examine differences in nociceptive mechanisms, pressure pain thresholds were also measured to evaluate changes in widespread pain sensitivity. RESULTS: Abdominal muscle activity related to random-bulb squeezing was rarely observed in healthy controls on menses (0.9 ± 0.6 episodes/hour) and in dysmenorrhea participants off menses (2.3 ± 0.6 episodes/hour). In dysmenorrheic participants during menses, abdominal muscle activity frequently preceded bulb squeezing indicative of menstrual cramping pain (10.8 ± 3.0 episodes/hour; P < .004). Whereas 45% of the women with dysmenorrhea (17 of 38) had episodes of abdominal muscle activity associated pain, only 13% (5 of 38) had episodes after naproxen (P = .011). Women with the abdominal muscle activity-associated pain were less likely to have a diagnosis for secondary dysmenorrhea or chronic pelvic pain (2 of 17) than women without this pain phenotype (10 of 21; P = .034). Similarly, women with the abdominal muscle activity-associated pain phenotype had less nonmenstrual pain days per month (0.6 ± 0.5) than women without the phenotype (12.4 ± 0.3; P = .002). Women with abdominal muscle activity-associated pain had pressure pain thresholds (22.4 ± 3.0 N) comparable with healthy controls (22.2 ± 3.0 N; P = .967). In contrast, women without abdominal muscle activity-associated pain had lower pressure pain thresholds (16.1 ± 1.9 N; P = .039). CONCLUSION: Abdominal muscle activity may contribute to cramping pain in primary dysmenorrhea but is resolvable with naproxen. Dysmenorrheic patients without cramp-associated abdominal muscle activity exhibit widespread pain sensitivity (lower pressure pain thresholds) and are more likely to also have a chronic pain diagnosis, suggesting their cramps are linked to changes in central pain processes. This preliminary study suggests new tools to phenotype menstrual pain and supports the hypothesis that multiple distinct mechanisms may contribute to dysmenorrhea.

Identification of experimental bladder sensitivity among dysmenorrhea sufferers.

BACKGROUND: Dysmenorrhea is a common risk factor for chronic pain conditions including bladder pain syndrome. Few studies have formally evaluated asymptomatic bladder pain sensitivity in dysmenorrhea, and whether this largely reflects excess pelvic symptom reporting due to comorbid psychological dysfunction. OBJECTIVE: We sought to determine whether bladder hypersensitivity is more common among women reporting moderate or greater dysmenorrhea, without chronic pain elsewhere, after accounting for anxiety and depression. Demonstrating this would suggest that dysmenorrhea might be an early clue for visceral or widespread pain hypersensitivity and improve understanding of potential precursors to bladder pain syndrome. STUDY DESIGN: We compared cohorts of regularly menstruating women, without symptoms of chronic pain elsewhere, reporting (1) moderate-to-severe dysmenorrhea (n = 98) and (2) low levels or no menstrual pain (n = 35). Participants underwent rapid bladder filling following a standard water ingestion protocol, serially rating bladder pain and relative urgency during subsequent distension. Potential differences in bladder volumes were controlled for by sonographic measurement at standard cystometric thresholds. Bladder sensitivity was also measured with complementary measures at other times separately including a simplified rapid filling test, palpation of the bladder wall, and through ambulatory self-report. Anxiety and depression were evaluated with the National Institutes of Health Patient-Reported Outcomes Measurement Information System measures. RESULTS: Women with moderate-to-severe dysmenorrhea reported more urinary symptoms than controls and had a lower maximum capacity (498 ± 18 mL vs 619 ± 34 mL, P < .001) and more evoked bladder filling pain (0-100 visual analog scale: 25 ± 3 vs 12 ± 3, P < .001). The dysmenorrhea-bladder capacity relationship remained significant irrespective of menstrual pain severity, anxiety, depression, or bladder pain (R2 = 0.13, P = .006). Severity of menstrual pain predicted evoked bladder pain (R2 = 0.10, P = .008) independent of anxiety (P = .21) and depression (P = .21). Women with moderate-to-severe dysmenorrhea exhibiting provoked bladder pain (24/98, 24%) also reported higher pain during the screening rapid bladder test (P < .001), in response to transvaginal bladder palpation (P < .015), and on prospective daily diaries (P < .001) than women with dysmenorrhea without provoked bladder pain. CONCLUSION: Women experiencing moderate-to-severe dysmenorrhea also harbor a higher pain response to naturally evoked bladder distension. Noninvasive bladder provocation needs to be tested further longitudinally in those with dysmenorrhea to characterize the course of visceral sensitivity and determine if it may help predict individuals at risk for developing subsequent pain in the bladder or elsewhere.