Emotional dysregulation in women with endometriosis with cyclical and non-cyclical chronic pelvic pain

Background: Endometriosis is a pathophysiological condition characterized by glands and stroma outside the uterus in regions such as the bladder, ureter, fallopian tubes, peritoneum, ovaries, and even in extra pelvic sites. One of the main clinical problems of endometriosis is chronic pelvic pain (CPP), which considerably affects the patients’ quality of life. Patients with endometriosis may, cyclically or non‑cyclically (80% of cases) experience CPP . High levels of anxiety and depression have been described in patients with endometriosis related to CPP; however, this has not been evaluated in endometriosis women with different types of CPP . Therefore, the research question of this study was whether there is a difference in the emotional dysregulation due to the type of pain experienced by women with endometriosis?

This work was performed in the National Institute of Perinatology (INPer) in Mexico City from January 2019 to March 2020 and aimed to determine if there are differences in emotional dysregulation in patients with cyclical and non‑cyclical CPP . 49 women from 18 to 52 years‑old diagnosed with endometriosis presenting cyclical and non‑cycli‑ cal CPP answered several batteries made up of Mini‑Mental State Examination, Visual Analog Scale, Beck’s Depression Inventory, State Trait‑Anxiety Inventory, and Generalized Anxiety Inventory. Mann–Whitney U and Student’s t‑test for independent samples to compare the difference between groups was used. Relative risk estimation was per‑ formed to determine the association between non‑cyclical and cyclical CPP with probability of presenting emotional dysregulation.

We observed that patients with non‑cyclical CPP exhibited higher levels of depression and anxiety (trait‑ state and generalized anxiety) than patients with cyclical pain, p < 0.05 was considered significant. No differences *Correspondence: [email protected]; [email protected]; [email protected] 1 Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología‑Facultad de Química, Universidad Nacional Autónoma de México, 04510 Mexico City, (CD MX), Mexico 2 Departamento de Neurociencias, Instituto Nacional de Perinatología, Av. Montes Urales # 800. Col. Lomas de Virreyes, 11000 Mexico City, CD MX, Mexico Full list of author information is available at the end of the article Page 2 of 9Rodríguez‑Lozano et al. BMC Women’s Health (2022) 22:525 were observed in pain intensity, but there was a higher probability of developing emotional dysregulation (anxiety or depression) in patients with non‑cyclical CPP . No differences were observed in cognitive impairment.

Our data suggest that patients with non‑cyclical (persistent) CPP present a higher emotional dysregu‑ lation than those with cyclical pain.

Chronic pelvic pain, Anxiety, Depression, Endometriosis, Menstrual cycle, Emotions

Endometriosis is a disease distinguished by a tissue simi - lar to the lining of the uterus growing outside it causing pain and infertility [1, 2]. 50% of infertile women exhibit endometriosis worldwide. Therefore, it is considered the most common gynecological disease in women of reproductive age and in perimenopausal women [3]. In Mexico, epidemiological reviews have estimated an endometriosis incidence of 34.5% in women diagnosed with primary and secondary infertility at the National Institute of Perinatology [4]. Endometriosis symptoms are infertility, dyspareunia, heavy menstrual bleeding, chronic fatigue, fibromyal - gia, migraine, and central sensitization syndrome [5–7]. However, the main clinical problem of endometriosis is chronic pelvic pain (CPP), which is defined as intermit - tent or constant pain in the lower abdomen or pelvis of at least six months, not occurring exclusively with menstru- ation or intercourse, and not associated with pregnancy [8, 9]. One of the most common causes of CPP in women is endometriosis (24–40%). Other associated condi - tions such as interstitial cystitis/bladder pain syndrome, chronic urinary tract infections, vulvodynia, irritable bowel syndrome, and inflammatory bowel disease may be comorbid with endometriosis [10–12]. CPP is a persistent and debilitating condition associ - ated with high costs and morbidity. Significant costs are associated with CPP , including absences from work, increased surgeries, and heavy burden to the health - care system [13]. CPP and infertility in women with endometriosis are associated with high levels of stress and uncertainty, reducing their quality of life and mak - ing challenging the performance of daily activities and the development of interpersonal relationships [14, 15]. Additionally, the difficulty experienced by these women from the onset of the first symptoms until diagnosis increases the probability of presenting emotional altera - tions. The average time between the onset of symptoms and the seeking help is from 3.7 to 5.7  years, extending up to 8 years for timely diagnosis [7, 16, 17]. The mechanisms by which CPP is generated in endo - metriosis have not been clearly defined. However, it occurs near endometriotic glands, and blood vessels in peritoneal endometriotic lesions innervated by sensory A delta, sensory C, cholinergic and adrenergic nerve fibers [18]. Nerve fiber densities are increased in the myometrium of women with endometriosis compared with those presented in women without this pathol - ogy [19, 20]. Although these nerve fibers may play an essential role in the mechanisms of pain generation in endometriosis, the emotional dysregulation can medi - ate the nociceptive experience by brain regions such as the anterior insula and the anterior cingulate cortex [21, 22]. Variable and broad symptoms and social implications of endometriosis have been considered disruptive to mental health, exhibiting high anguish, anxiety, depres - sion, and chronic stress [23– 26]. It has been described that the presence of CPP affects mental health [14], regardless of endometriosis stage or type [27], and it did not always decrease after medical treatment or sur - gery. Patients with endometriosis may experience CPP cyclically or non-cyclically (80% of cases) defined as non-menstrual pain [28, 29]; however, whether there is a difference in levels of anxiety and depression between these two patient groups has not been evaluated. There - fore, it is not known how different CPP affects the emo - tional state of women with endometriosis. This study aimed to determine if there are differences in emotional dysregulation in patients with cyclic and non-cyclic C P P.

Design of the study We conducted a transversal study at the National Insti - tute of Perinatology (INPer, Neuroscience Department, Mexico City) from January 2019 to March 2020. Approval from the Institution Ethical and Scientific Committee was obtained before the beginning of the study (reference number: INPer, 2019–1-51). Women with endometriosis were invited to participate in the study when coming to their gynecology interview at Department of Gynecology at INPer. Patients who voluntary participated in the study were requested to sign a written informed consent. During the initial interviews at the Gynecology and Neuroscience Departments, we assessed the patients’ eli- gibility according to the inclusion criteria. Participants gynecological, sociodemographic, and psychological characteristics were recorded in a database. Page 3 of 9 Rodríguez‑Lozano et al. BMC Women’s Health (2022) 22:525 Participants Patients recruited into the study were attending at the Gynecology Department in the INPer. The recruited population comprised women from 18 to 52 years old with a diagnosis of endometriosis (by laparoscopic or magnetic resonance) and CPP for at least 1  year. The medical staff carried out a complete clinical evalua - tion and an analysis of sociodemographic variables was done, including marital status, education level, and working status. Participants were asked to complete self-reported questionnaires used to measure cogni - tive impairment, the intensity of pelvic pain, general discomfort, depression, and anxiety: Mini-Mental State Examination (MMSE), Visual Analog Scale (VAS), Beck Depression Inventory (BDI), State-Trait Anxiety Inven - tory (STAI) and Generalized Anxiety Disorder Screener (GAD). Fifty-four patients were recruited, but 5 were dis - carded for not completing evaluations. Forty-nine par - ticipants were included in the study and divided into two groups according to the type of CPP they experi - enced. If the patient suffered from CPP only during her menstrual period, she was classified in the cyclical CPP group (n = 21), if the patient presented persistently CPP regardless of the menstrual phase, she was classified in the group of non-cyclical CPP group (n = 28). A psy - chometric evaluation was performed when the patients with cyclical CPP were in the menstrual phase, while the patients with non-cyclical pain reported permanent pain during the menstrual phase. Then, the evaluation was performed in the same phase of the cycle. Instruments The Mini-Mental State Examination (MMSE) is a test used to detect mild cognitive impairment through tests of orientation, memory, attention, calculation, and lan - guage. If the score is ≤ 24, probable cognitive impairment is suspected and if it is > 24, the result was "without cog - nitive impairment" [30]. Wong-Baker FACES ® Pain Rating Scale is a visual analog scale (VAS) that self-reported the intensity of CPP . The scale is made up of six faces drawn with ratings from 0 to 10, where 0 is equivalent to the minimum pain and 10 to the maximum pain that have experienced [31]. Beck Depression Inventory (BDI) is a 21-item meas - ure of depression equivalent to the Diagnostic and Sta - tistical Manual of Mental Disorders (DSM) symptoms of depression [32]. Patients chose their responses on a 0–3 Likert-type scale. Scores of BDI can range from 0 to 63 with the following cut- offs: 0–13, minimally depressed; 14–19, mildly depressed, 20–28, moderately depressed, and 29–63, severely depressed [33, 34]. State-Trait Anxiety Inventory (STAI) is used to meas - ure two different dimensions of anxiety: State Anxiety Scale evaluated the current state of anxiety, asking how patients feel “right now”; and Trait Anxiety Scale evalu - ated relatively stable aspects of “anxiety proneness” [35]. Scores of both scales range from 20 to 80. Scores between 20 and 31 indicated minimal anxiety, 32 to 43 mild anxi - ety, 44 to 55 moderate anxiety, 56 to 67 severe anxiety, and 68 to 80 maximum anxiety [36]. Generalized Anxiety Disorder Screener (GAD) is a 7-item self-report for screening of Generalized Anxi - ety Disorder which are rated on a 4-point Likert-type indicating symptom frequency, ranging from 0 (not at all sure) to 3 (nearly every day), yielding a value in the response range from 0 to 21 points. Higher scores indi - cate higher levels of GAD symptoms [37]. All the instru - ments have been translated to the local language and validated in the local setting [33, 36, 37]. Statistical analysis Demographic parameters and sociomedical conditions were expressed as mean ± SD or N (%), Bonferroni’s cor- rection was used to reduce type 1 error. Inferential analy- sis was performed with a chi-square (nominal variables), Mann–Whitney U (ordinal variables), and Student’s t-test for independent samples (scalar variables) to compare the difference between groups. Relative risk estimation was performed to determine the association between non-cyclical and cyclical CPP with probability of present- ing emotional dysregulation. Statistical analyzes were performed with SPSS v.24.0 software (Armonk, New York: IBM Corp). For all statistical analyses, p < 0.05 was considered significant.

Demographics characteristics Table 1 shows the sociodemographic characteristics of women with endometriosis with cyclical (n = 21) and non-cyclical CPP (n = 28). There were no differences in age, years of study, working status and marital status between the two groups. However, results indicate that only 23.8% of women with cyclic pain and 53.5% with non-cyclical pain were married or cohabiting. Medical characteristics of patients are described in Table 2. The percentage of nulliparous women is higher in women with non-cyclical CPP (78.6%) than in cycli - cal CPP women (45.6%). In both cases about 60% of patients report disabling pain for about 10  years and more than 70% of all women described at least another symptom associated with endometriosis. Most patients in both groups have received at least one surgery to manage symptoms including cleaning of endometrial focuses by laparoscopy (conservative surgery), which Page 4 of 9Rodríguez‑Lozano et al. BMC Women’s Health (2022) 22:525 was the most common surgery in these patients. Addi - tionally, all women reported consumption of some drug for the endometriosis symptoms, mainly non-steroidal anti-inflammatory drugs (NSAIDs). No differences were found in disabling CPP perception, years reporting disa - bling pain, other presenting symptoms, previous surgery endometriosis, or disruptions, comorbidities between women with cyclical and non-cyclical pain. To determine differences in global scores on psycho - metric scales applied between endometriosis patients with cyclical and non-cyclical CPP , a normal distribution of the results was corroborated with the Shapiro wilk test for n ≥ 30 and Levene’s test showed equality of variances. Then, the global scores of each scale were analyzed using a Student’s t test for independent samples. The global scores obtained in depression, anxiety as a trait and state, and generalized anxiety were higher in women with non- cyclical chronic pain than in those with cyclical pain (Table 3). Student’s t test for cognitive impairment could not be calculated because the standard deviation of both groups was equal to 0. To determine differences in pain perception and emo - tional dysregulation between patients with cyclical and non-cyclical CPP according to the clinical classification of each psychometric scales, a Mann–Whitney U test was performed. Most patients with non-cyclical pelvic pain exhibited mild state anxiety (α = 0.007) and depression from mild to severe (α = 0.018) compared to women with cyclical CPP that presented a lower emotional affectation (Fig.  1). No differences were observed in pain intensity, anxiety as a trait or generalized anxiety according to the clinical classification. However, it was found that 70% of endometriosis women with cyclical CPP and more than 90% of the non-cyclical population reported severe to maximum pain; and more than 60% of patients with non- cyclic pain presented mild to severe generalized anxiety. A relative risk estimation was performed to determine the association between non-cyclical or cyclical CPP and the probability of presenting depression or anxiety as risk factors. Results demonstrated a significant relative risk (> 1) in depression (4.5) and state anxiety (2.85) in patients with non-cyclical pain. Relative risk of patients with cyclical chronic pain was not significant (Table 4).

Endometriosis is a long-term, disabling medical con - dition that affects the quality of life and mental health associated with CPP . Patients with endometriosis may experience CPP in a cyclical manner such as dysmenor - rhea or in a noncyclical manner defined as non-menstrual pain. Several reports suggest that chronic experience of pain increases emotional dysregulation [38–40] and that psychiatric disorders are more common among women with endometriosis [41–44], however, differences in emo- tional dysregulation based on CPP experience in women with endometriosis had not been explored. Therefore, the objective of this study was to determine if there are differences in the levels of emotional dysregulation in patients with cyclical and non-cyclical CPP . This is one of the few studies carried out in Latin America where spe - cialized endometriosis care centers are very limited [29, 45]. High levels of depression and anxiety were found in both groups of patients with CPP , which coincided with previous studies [41–44], however, the present work is the first one in demonstrating higher global scores in depression, anxiety as a trait and state, and general - ized anxiety in women with non-cyclical CPP . In addi - tion, more women with endometriosis experiencing non-cyclic CPP suffered from mild to severe depression and mild state anxiety compared to women experienc - ing cyclical pain. Menorrhagia and persistent pain are two variables that may be associated with greater emo - tional dysregulation, however, in this study, patients with cyclical pain did not show a difference in the frequency of these symptoms compared to patients with non- cyclical pain [46, 47]. However, it is essential to consider the complexity of the disease and the emotional care of these women to improve their quality of life. Relative risk estimation associated with pain intensity determined Table 1 Sociodemographic characteristics of endometriosis women with CPP The parametric t‑test was used to detect statistical differences between demographic measures age, years of study. The chi‑square test was used to determine differences in marital status, working status between women with cyclical and non‑cyclical pain. Bonferroni´s correction was used. n = 49 Participants Cyclical pain Non-cyclical pain p-value n = 49 n = 21 n = 28 Age Mean (SD) Mean (SD) .80 35.2 (6.9) 34.7 (6.47) Marital status N (%) N (%) .36 Never married 15 (71.4) 10 (35.7) Married 3 (14.3) 9 (32.1) Divorced 1 (4.8) 3 (10.7) Cohabiting 2 (9.5) 6 (21.4) Years of study Mean (SD) Mean (SD) .40 14.4 (3.4) 15.1 (3.13) Working status N (%) N (%) .96 Employee 5 (23.8) 5 (17.9) Unemployed 2 (9.5) 4 (14.3) Home labor 5 (23.8) 7 (25) Commerce 3 (9.5) 4 (14.3) Profession 4 (19.4) 6 (21.4) Study 1 (4.8) 2 (7.1) Page 5 of 9 Rodríguez‑Lozano et al. BMC Women’s Health (2022) 22:525 Table 2 Medical conditions of endometriosis women with CPP Cyclical pain Non-cyclical pain p-value Paritya N (%) N (%) .024* Nulliparous 10 (45.6) 22 (78.6) ≥ 1 11 (52.4) 6 (21.4) Disabling CPP perception N (%) N (%) .61 Yes 12 (57.1) 18 (64.3) No 9 (42.9) 10 (35.7) Years reporting disabling CPP Mean (SD) Mean (SD) .51 9.38 (8.36) 10.8 (8.10) Other symptomsa N (%) N (%) No otherb 7 (33.3) 7 (25) .52 Menorrhagia 6 (28.6) 14 (50) .131 Dyspareunia 7 (33.3) 10 (35.7) .862 Widespread pain 2 (9.52) 4 (14.3) .615 Amenorrhea 2 (9.52) 3 (10.7) .892 Chronic fatigue 1 (4.76) 4 (14.3) .276 Inflammation 4 (19.0) 1 (3.57) .077 Rectal tenesmus 0 2 (7.14) .211 Infertility 0 2 (7.10) ..211 Dysuria 1 (4.76) 1 (3.57) .835 Premenstrual dysphoria 1 (4.76) 0 .243 Subinfertility 1(4.8) 0 .73 Previous endometriosis surgery N (%) N (%) .84 0 6 (28.6) 8 (28.6) 1 9 (42.9) 10 (35.7) ≥ 2 6 (28.6) 10 (35.7) Surgery for endometriosisa N (%) N (%) Endometrial focuses 5 (23.8) 9 (32.1) .52 Oophorectomy 6 (28.6) 5 (17.9) .37 Hysterectomy 3 (14.3) 5 (17.9) .74 Colectomy 2 (9.52) 1 (3.57) .39 Pharmacotherapya N (%) N (%) NSAIDsc 15 (71.4) 26 (92.9) .04 Hormones 7 (33.3) 8 (28.6) .72 Antispasmodic 1 (4.8) 3 (10.7) .45 Anxiolytics 2 (9.52) 2 (7.14) .76 Opioid analgesic 2 (9.52) 0 .09 Cannabis 0 2 (7.14) .21 Disruptionsa N (%) N (%) None 9 (42.9) 5 (17.8) .11 Work/School 5 (23.8) 10 (35.7) .37 Relationship 6 (28.6) 8 (28.6) 1 Next surgery 5 (23.8) 6 (21.4) .84 Social 3 (14.3) 5 (17.9) .74 Desire to be a mother 3 (14.3) 4 (14.3) 1 Family 0 5 (17.9) .07 Economy 1 (4.76) 1 (3.57) .83 Comorbiditiesa N (%) N (%) None 10 (47.6) 19 (67.9) .15 Polycystic ovary 3 (14.3) 3 (10.7) .71 Page 6 of 9Rodríguez‑Lozano et al. BMC Women’s Health (2022) 22:525 a higher probability of developing depression, and state anxiety in patients with non-cyclical pain. In fact, the risk of presenting emotional disturbances is more than doubled in the group of women with noncyclic pain than in those with cyclical pain, which gives us clinically sig - nificant and relevant data for the diagnosis and manage - ment of these patients [48, 49]. Pain intensity was assessed using the VAS, since it has been shown to be effective for most patients with endometriosis (64%) during the painful experience and indeed, one month after the experience [50]. However, no statistically significant differences were found in inten - sity of pain between CPP groups. In both cases most patients report severe to maximum pain and perceive it as a disabling pain for about a decade, which could sig - nificantly affect their quality-of-life [51]. The relationship between reports of pain and physical pathology is still debated. Authors suggest a complete evaluation of the pain considering location, duration, sensory and affective Table 2 (continued) Cyclical pain Non-cyclical pain p-value Hypothyroidism 3 (14.3) 0 .04 Myomatosis 3 (14.3) 0 .04 Adenomyosis 2 (9.52) 1 (3.57) .39 Overactive bladder 2 (9.52) 0 .09 Obesity 0 1 (3.57) .38 Anemia 0 1 (3.57) .38 Heart disease 1 (4.76) 0 .24 The parametric t‑test was used to detect statistical differences between years reporting disabling CPP . The chi‑square test was used to determine differences disabling CPP , parity, other presenting symptoms, previous surgery for endometriosis, pharmacotherapy, disruptions, and comorbidities between women with cyclical and non‑ cyclical pain. n = 49; *p < 0.05. Bonferroni´s correction was used a Different options can be associated with the same patient b No other symptoms of endometriosis besides CPP c NSAIDs, Non‑steroidal anti‑inflammatory drugs Table 3 Cognitive impairment, pain perception, and emotional dysregulation global scores in endometriosis women with cyclical and non‑cyclical pain Table shows the mean ± SD, n = 49, *p < 0.05 Type of chronic pelvic pain Cyclical Non-cyclical p-value Cognitive impairment 28.80 (1.28) 28.35 (1.06) .11 Pain intensity 7.90 (2.79) 8.85 (1.48) .13 Depression 11.14 (2.42) 17.46 (1.92)* .04 Trait anxiety 37.42 (3.23) 47 (2.02)* .01 State anxiety 39.33 (2.52) 47.35 (1.89)* .02 Generalized anxiety 5.14 (1.08) 8.46 (1.05)* .03 Fig. 1 Pain perception and emotional dysregulation in endometriosis women with cyclical and non‑cyclical pelvic pain. n = 49, **p < 0.01 Page 7 of 9 Rodríguez‑Lozano et al. BMC Women’s Health (2022) 22:525 description, functional status in daily activities [52]; and the hours or sleep disturbances derived from pain [23]. Besides, Api [53] highlights that other symptoms of endometriosis such as painful intercourse or dyspareunia can mediate the intensity of CPP; however, in this study no differences were found in other symptoms of endo - metriosis between patients with cyclical and non-cyclical pain. For the management of endometriosis symptoms, all the patients reported drug use, mainly analgesics. Because cognitive impairment is common in patients with chronic pain for excessive use of analgesics includ - ing opioids, increased vulnerability to endocrine dis - rupting chemicals, and age-related cognitive decline [54–56], MMSE test was applied. However, no cogni - tive impairment was found in women with endometrio - sis using MMSE. Nevertheless, cognitive impairments were reported by Wassink [57], through EGG and event- related potentials in these patients. It is recommended to explore specific cognitive functions with neuropsycho - logical batteries to improve rehabilitation for future stud- ies [58]. In this study, most patients reported disruptions associ- ated with symptoms of endometriosis, at work, relation - ships and family. In addition, it was observed that most women with cyclical pain had not been married, and most women with non-cyclical pain do not have children. Low social support and family networks must maintain depressive and anxious states [59, 60], so women with endometriosis may be more vulnerable to living with chronic emotional dysregulation, which is associated with low quality of life [45]. Marital status and number of children are not predictors of emotional well-being in midlife in women, but rather the quality of relationships [51, 61, 62]. Intensity of pain and emotional dysregula - tion in women with endometriosis can be mediated by psychosocial variables such as emotional suppression, pain catastrophism, personality, and a passive coping style, which can also affect patients’ interactions [63–65]. Different comorbid conditions have been implicated in CPP in endometriosis, such as pelvic floor tender - ness, painful bladder syndrome, sexual assault, higher body mass index, current smoking, physical activity, depression, and anxiety [66, 67]. This is the first study that describes differences in emotional dysregulation according to the type of CPP experienced by patients with endometriosis. Therefore, continued research is required to validate these psychosocial factors and deter - mine if any of them is potentially modifiable for improv - ing the quality of life of women with endometriosis.

Our data suggest that non-cyclical (persistent)  CPP is associated with a higher emotional dysregulation than those with cyclical pain women with endometriosis, and that non-cyclical CPP may make patients more vulner - able to developing emotional dysregulation. Abbreviations CPP: Chronic pelvic pain; INPer: National Institute of Perinatology; MMSE: Mini‑Mental State Examination; VAS: Visual Analog Scale; BDI: Beck Depression Inventory; DSM: Diagnostic and Statistical Manual of Mental Disorders; STAI: State‑Trait Anxiety Inventory; GAD: Screener; NSAIDs: Non‑steroidal anti‑ inflammatory drugs.

This study was supported by INPer Project No. 2019‑1‑51, and by CONACYT for the first author’s doctoral grant, no. 749741 with scholarship number (CVU) 780154. Authors’ contributions MPMR designed and conducted the study. DCRL wrote the body of the manuscript. ICA and BDT were major contributors in reviewing the data and body of the manuscript and amending several areas of the manuscript. OPCO, BSR, AOO, JRST, GCB, LFEP conducted the clinical intervention in women with endometriosis to assesses the recruitment of patients into the study. DCRL and MPMR applied and scored the psychometric instruments to the participants. DCRL, MPMR and JMSP contributed to the statistical analysis of data. The author(s) read and approved the final manuscript. Funding This study was supported by INPer Project No. 2019–1‑51, and by CONACYT for the first author’s doctoral grant, No. 74974 1with scholarship number (CVU) 780154. Availability of data and materials The datasets generated and/or analyzed during the current study are not pub‑ licly available due institutional policies but are available from the correspond‑ ing author on reasonable request. Declarations Ethics approval and consent to participate We received the approval of the clinical study from the head of the Ethical and Research Committee of National Institute of Perinatology, Isidro Espinosa de los Reyes, (Montes Urales # 800, Col Lomas de Virreyes, 11000, CD MX, Mexico) with the project No. 20191–51. The written Informed Consent was Table 4 Relative risks of patients with cyclical and non‑cyclical pain Table shows relative risk scores and SD a Represents a significant relative risk (> 1). n = 49 Type of CPP Depression Trait anxiety State anxiety Generalized anxiety Cyclical 0.23 (0.07–0.66) 0.44 (0.16–1.18) 0.35 (0.15–0.78) 0.54 (0.28–1.07) Non-cyclical 4.25 (1.43–12.6)a 2.25 (0.88–5.99) 2.85 (1.27–6.38)a 1.82 (0.92–3.57) Page 8 of 9Rodríguez‑Lozano et al. BMC Women’s Health (2022) 22:525 also obtained from all participants recruited in the present study All methods were performed in accordance with the relevant guidelines and regulations in compliance with the Helsinki Declaration. Consent for publication Not applicable Competing interests The authors declare that they have no competing financial and non‑financial interests that could influence the publishing of the final version of the manuscript. Author details 1 Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología‑Facultad de Química, Universidad Nacional Autónoma de Méx‑ ico, 04510 Mexico City, (CD MX), Mexico. 2 Departamento de Neurociencias, Instituto Nacional de Perinatología, Av. Montes Urales # 800. Col. Lomas de Virreyes, 11000 Mexico City, CD MX, Mexico. 3 Departamento de Ginecología, Instituto Nacional de Perinatología, Mexico City, Mexico. 4 Departamento de Genética y Genómica Humana, Instituto Nacional de Perinatología, Mexico City, Mexico. 5 Facultad de Psicología, Universidad Nacional Autónoma de México, Mexico City, Mexico. Received: 30 June 2022 Accepted: 11 November 2022

1. Surrey E, Carter CM, Soliman AM, Khan S, Di Benedetti DB, Snabes MC. Patient‑completed or symptom‑based screening tools for endometriosis: a scoping review. Arch Gynecol Obstet. 2017;296(2):153–65. https:// doi. org/ 10. 1007/ s00404‑ 017‑ 4406‑9. 2. World Health Organization (WHO). International Classification of Diseases, 11th Revision (ICD‑11). WHO: Geneva; 2018. 3. National Guideline Alliance (UK). Endometriosis: diagnosis and manage‑ ment. London: National Institute for Health and Care Excellence (NICE); 2017. 4. Preciado Ruiz R, Torres Calleja J, ZúñigaMontiel JA, MartínezChéquer JC, Manterola Alvarez D, García LA. Incidencia de la endometriosis en mujeres con infertilidad: características clínicas y laparoscópicas [Incidence of endometriosis in infertile women: clinical and laparoscopic characteristics]. Ginecol Obstet. 2005;73(9):471–6. 5. Nnoaham KE, Hummelshoj L, Webster P , d’Hooghe T, de Cicco Nardone F, de Cicco Nardone C, Jenkinson C, Kennedy SH, Zondervan KT, World Endometriosis Research Foundation Global Study of Women’s Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96(2):366‑373.e8. https:// doi. org/ 10. 1016/j. fertn stert. 2011. 05. 090. 6. Agarwal SK, Chapron C, Giudice LC, Laufer MR, Leyland N, Missmer SA, Singh SS, Taylor HS. Clinical diagnosis of endometriosis: a call to action. Am J Obstet Gynecol. 2019;220(4):354.e1‑354.e12. https:// doi. org/ 10. 1016/j. ajog. 2018. 12. 039. 7. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382(13):1244–56. https:// doi. org/ 10. 1056/ NEJMr a1810 764. 8. International Association for the Study of Pain (IASP). Classification of Chronic Pain, Second Edition (Revised) consulted on March 18, 2022, https:// www. iasp‑ pain. org/ advoc acy/ global‑ year/ trans lating‑ pain‑ knowl edge‑ to‑ pract ice/ 9. Vincent K. Chronic pelvic pain in women. Postgrad Med J. 2009;85(999):24–9. https:// doi. org/ 10. 1136/ pgmj. 2008. 073494. 10. Jarrell JF, Vilos GA, Allaire C, Burgess S, Fortin C, Gerwin R, Lapensée L, Lea RH, Leyland NA, Martyn P , Shenassa H, Taenzer P , Abu‑Rafea B; Chronic Pelvic Pain Working Group; SOGC. Consensus guidelines for the manage‑ ment of chronic pelvic pain. J Obstet Gynaecol Can. 2005;27(8):781–826. English, French. https:// doi. org/ 10. 1016/ s1701‑ 2163(16) 30732‑0. 11. Ayorinde AA, Macfarlane GJ, Saraswat L, Bhattacharya S. Chronic pelvic pain in women: an epidemiological perspective. Womens Health (Lond). 2015;11(6):851–64. https:// doi. org/ 10. 2217/ whe. 15. 30. 12. Johnson NP , Hummelshoj L, Adamson GD, Keckstein J, Taylor HS, Abrao MS, Bush D, Kiesel L, Tamimi R, Sharpe‑Timms KL, Rombauts L, Giudice LC, World Endometriosis Society Sao Paulo Consortium. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 2017;32(2):315–24. https:// doi. org/ 10. 1093/ humrep/ dew293. 13. Ahangari A. Prevalence of chronic pelvic pain among women: an updated review. Pain Physician. 2014;17(2):141–7. 14. Facchin F, Barbara G, Saita E, Mosconi P , Roberto A, Fedele L, Vercellini P . Impact of endometriosis on quality of life and mental health: pelvic pain makes the difference. J Psychosom Obstet Gynaecol. 2015;36(4):135–41. https:// doi. org/ 10. 3109/ 01674 82X. 2015. 10741 73. 15. Pérez‑López FR, Ornat L, Pérez‑Roncero GR, López‑Baena MT, Sánchez‑ Prieto M, Chedraui P . The effect of endometriosis on sexual function as assessed with the Female Sexual Function Index: systematic review and meta‑analysis. Gynecol Endocrinol. 2020;36(11):1015–23. https:// doi. org/ 10. 1080/ 09513 590. 2020. 18125 70. 16. Culley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten M, Raine‑ Fenning N. Tehe social and psychological impact pf endometriosis on women’s lives: a critical narrative review. Hum Reprod Update. 2013;19(6):625–39. 17. Armour M, Sinclair J, Ng CHM, Hyman MS, Lawson K, Smith CA, Abbott J. Endometriosis and chronic pelvic pain have similar impact on women, but time to diagnosis is decreasing: an Australian survey. Sci Rep. 2020;10(1):16253. https:// doi. org/ 10. 1038/ s41598‑ 020‑ 73389‑2. 18. Wang G, Tokushige N, Markham R, Fraser IS. Rich innervation of deep infiltrating endometriosis. Hum Reprod. 2009;24(4):827–34. https:// doi. org/ 10. 1093/ humrep/ den464. 19. Tokushige N, Markham R, Russell P , Fraser IS. Nerve fibres in peritoneal endometriosis. Hum Reprod. 2006;21(11):3001–7. https:// doi. org/ 10. 1093/ humrep/ del260. 20. Miller EJ, Fraser IS. The importance of pelvic nerve fibers in endometriosis. Womens Health (Lond). 2015;11(5):611–8. https:// doi. org/ 10. 2217/ whe. 15. 47. 21. Benarroch EE. What is the role of the cingulate cortex in pain? Neurology. 2020;95(16):729–32. https:// doi. org/ 10. 1212/ WNL. 00000 00000 010712. 22. Vogt BA. Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci. 2005;6(7):533–44. https:// doi. org/ 10. 1038/ nrn17 04. PMID: 15995724. 23. Facchin F, Barbara G, Dridi D, Alberico D, Buggio L, Somigliana E, Saita E, Vercellini P . Mental health in women with endometriosis: searching for predictors of psychological distress. Hum Reprod. 2017;32(9):1855–61. https:// doi. org/ 10. 1093/ humrep/ dex249. 24. Denny E. I never know from one day to another how I will feel: pain and uncertainty in women with endometriosis. Qual Health Res. 2009;19(7):985–95. https:// doi. org/ 10. 1177/ 10497 32309 338725. 25. Casalechi M, Vieira‑Lopes M, Quessada MP , Arão TC, Reis FM. Endometrio‑ sis and related pelvic pain: association with stress, anxiety and depressive symptoms. Minerva Obstet Gynecol. 2021;73(3):283–9. https:// doi. org/ 10. 23736/ S2724‑ 606X. 21. 04704‑3. 26. Siedentop F, Tariverdian N, Rücke M, Kentenich H, Arck PC. Immunes status, psychosocial distress and reduces quality of life in infertile patients with endometriosis. Am J Reprod Immunol. 2008;5:449–61. 27. Vercellini P , Fedele L, Aimi G, Pietropaolo G, Consonni D, Crosignani PG. Association between endometriosis stage, lesion type, patient character‑ istics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007;22(1):266–71. https:// doi. org/ 10. 1093/ humrep/ del339. 28. Ball E, Khan KS. Recent advances in understanding and managing chronic pelvic pain in women with special consideration to endometriosis. F1000Res. 2020;9:F1000 Faculty Rev‑83. https:// doi. org/ 10. 12688/ f1000 resea rch. 20750.1. 29. Latthe P , Latthe M, Say L, Gülmezoglu M, Khan KS. WHO systematic review of prevalence of chronic pelvic pain: a neglected reproductive health morbidity. BMC Public Health. 2006;6:177. https:// doi. org/ 10. 1186/ 1471‑ 2458‑6‑ 177. 30. Beaman S, Beaman P García‑Peña C, Villa M, Heres J, Córdova A, Jagger C. Validation of a modified version of the Mini‑Mental State Examination (MMSE) in spanish. Aging Neuropsychol Cogn. 2004;11(1):1–11. https:// doi. org/ 10. 1076/ anec. 11.1. 1. 29366. 31. Orella J, Morales‑Castillo V, Gonzalez‑Osorio M. Visual analogue Scale Wong‑Baker´s Face Pain Rating Scale and Pain. Salud y Administración. 2018;5:61–7. Page 9 of 9 Rodríguez‑Lozano et al. BMC Women’s Health (2022) 22:525 32. Beck AT, Steer RA, Brown GK. Manual for the BDI‑II. San Antonio, TX: Psychological Corporation; 1996. 33. González DA, Reséndiz A, Reyes‑Lagunes I. Adaptation of the BDI‑II in Mexico. Salud Ment. 2015;38(4):237–44. https:// doi. org/ 10. 17711/ SM. 0185‑ 3325. 2015. 033. 34. Steer RA, Clark DA, Beck AT, Ranieri WF. Common and specific dimen‑ sions of self‑reported anxiety and depression: the BDI‑II versus the BDI‑IA. Behav Res Ther. 1999;37(2):183–90. https:// doi. org/ 10. 1016/ s0005‑ 7967(98) 00087‑4. 35. Julian LJ. Measures of anxiety: State‑Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), and Hospital Anxiety and Depression Scale‑ Anxiety (HADS‑A). Arthritis Care Res (Hoboken). 2011;63 Suppl 11(0 11):S467‑72. https:// doi. org/ 10. 1002/ acr. 20561. 36. Urdapilleta‑Herrera Edel C, Sansores RH, Ramírez‑Venegas A, Méndez‑ Guerra M, Lara‑Rivas AG, Guzmán‑Barragán SA, Ayala‑Guerrero F, Haro‑Valencia R, Cansino S, Moreno‑Coutiño A. Anxiety and depression in Mexican smokers, and their relationship with the severity of addiction. Salud Publica Mex. 2010;52(Suppl 2):S120–8. 37. Soto‑Balbuena C, Rodríguez‑Muñoz MF, Le HN. Validation of the General‑ ized Anxiety Disorder Screener (GAD‑7) in Spanish Pregnant Women. Psicothema. 2021;33(1):164–70. https:// doi. org/ 10. 7334/ psico thema 2020. 167. 38. Tauben D. Chronic pain management: measurement‑based step care solutions. Pain. 2012;20(8):1‑7. 39. Pinto PR, McIntyre T, Almeida A, Araújo‑Soares V. The mediating role of pain catastrophizing in the relationship between presurgical anxiety and acute postsurgical pain after hysterectomy. Pain. 2012;153(1):218–26. 40. Che X, Cash R, Fitzgerald P , Fitzgibbon BM. The Social Regulation of Pain: Autonomic and Neurophysiological Changes Associated With Perceived Threat. J Pain. 2018;19(5):496–505. 41. Laganà AS, La Rosa VL, Rapisarda AMC, Valenti G, Sapia F, Chiofalo B, Ros‑ setti D, Ban Frangež H, VrtačnikBokal E, Vitale SG. Anxiety and depression in patients with endometriosis: impact and management challenges. Int J Womens Health. 2017;16(9):323–30. https:// doi. org/ 10. 2147/ IJWH. S1197 29. PMID:28553145;PMCID:PMC5440042. 42. Gao M, Koupil I, Sjöqvist H, Karlsson H, Lalitkumar S, Dalman C, Kosidou K. Psychiatric comorbidity among women with endometriosis: nationwide cohort study in Sweden. Am J Obstet Gynecol. 2020;223(3):415.e1‑415. e16. https:// doi. org/ 10. 1016/j. ajog. 2020. 02. 033. 43. Van Barneveld E, Manders J, van Osch FHM, van Poll M, Visser L, van Hanegem N, Lim AC, Bongers MY, Leue C. Depression, Anxiety, and Cor‑ relating Factors in Endometriosis: A Systematic Review and Meta‑Analysis. J Womens Health (Larchmt). 2022;31(2):219–30. https:// doi. org/ 10. 1089/ jwh. 2021. 0021. 44. Casalechi M, Vieira‑Lopes M, Quessada MP , Arão TC, Reis FM. Endometrio‑ sis and related pelvic pain: association with stress, anxiety and depressive symptoms. Minerva Obstet Gynecol. 2021;73(3):283–9. https:// doi. org/ 10. 23736/ S2724‑ 606X. 21. 04704‑3. 45. He G, Chen J, Peng Z, Feng K, Luo C, Zeng X. A Study on the Correlation Between Quality of Life and Unhealthy Emotion Among Patients With Endometriosis. Front Psychol. 2022;14(13):830698. https:// doi. org/ 10. 3389/ fpsyg. 2022. 830698. 46. Chapa HO, Venegas G, Antonetti AG, Van Duyne CP , Sandate J, Bakker K. In‑office endometrial ablation and clinical correlation of reduced menstrual blood loss and effects on dysmenorrhea and premenstrual symptomatology. J Reprod Med. 2009;4:232–8. PMID: 19438165. 47. Grundström H, Gerdle B, Alehagen S, Berterö C, Arendt‑Nielsen L, Kjølhede P . Reduced pain thresholds and signs of sensitization in women with persistent pelvic pain and suspected endometriosis. Acta Obstet Gynecol Scand. 2019;98(3):327–36. https:// doi. org/ 10. 1111/ aogs. 13508. Epub 2018 Dec 30 PMID: 30472739. 48. Evans S, Fernandez S, Olive L, Payne LA, Mikocka‑Walus A. Psychological and mind‑body interventions for endometriosis: a systematic review. J Psychosom Res. 2019;124:109756. https:// doi. org/ 10. 1016/j. jpsyc hores. 2019. 109756. 49. Mechsner S. Endometriosis, an Ongoing Pain‑Step‑by‑Step Treatment. J Clin Med. 2022;11(2):467. https:// doi. org/ 10. 3390/ jcm11 020467. 50. Nunnink S, Meana M. Remembering the pain: accuracy of pain recall in endometriosis. J Psychosom Obstet Gynaecol. 2007;28(4):201–8. https:// doi. org/ 10. 1080/ 01674 82070 13887 81. 51. Olliges E, Bobinger A, Weber A, Hoffmann V, Schmitz T, Popovici RM, Meissner K. The Physical, Psychological, and Social Day‑to‑Day Experience of Women Living With Endometriosis Compared to Healthy Age‑ Matched Controls‑A Mixed‑Methods Study. Front Glob Womens Health. 2021;2:767114. https:// doi. org/ 10. 3389/ fgwh. 2021. 767114. 52. Cid JC, Acuña BJ, de Andrés AJ, Díaz JL, Gómez CA. ¿Qué y cómo evaluar al paciente con dolor crónico? evaluación del paciente con dolor crónico. Rev Méd Clín Condes. 2014;25(4):687–97. 53. Api M, Boza AT, Kayatas S, Eroglu M. Effect of Surgical Removal of Endometriomas on Cyclic and Non‑cyclic Pelvic Pain. Int J Fertil Steril. 2015;9(2):183–8. https:// doi. org/ 10. 22074/ ijfs. 2015. 4252. 54. Altiparmak B, Güzel Ç, Gümüş DS. Comparison of Preoperative Admin‑ istration of Pregabalin and Duloxetine on Cognitive Functions and Pain Management After Spinal Surgery: A Randomized, Double‑blind. Placebo‑controlled Study Clin J Pain. 2018;34(12):1114–20. https:// doi. org/ 10. 1097/ AJP . 00000 00000 000640. 55. Kahn LG, Philippat C, Nakayama SF, Slama R, Trasande L. Endocrine‑ disrupting chemicals: implications for human health. Lancet Diabetes Endocrinol. 2020;8(8):703–18. https:// doi. org/ 10. 1016/ S2213‑ 8587(20) 30129‑7. 56. Sörös P , Bantel C. Chronic noncancer pain is not associated with acceler‑ ated brain aging as assessed by structural magnetic resonance imaging in patients treated in specialized outpatient clinics. Pain. 2020;161(3):641– 50. https:// doi. org/ 10. 1097/j. pain. 00000 00000 001756. 57. Wassink K, De Blasio FM, Fogarty JS, Cave AE, Love S, Armour M. Neuronal Correlates of Cognitive Control Are Altered in Women With Endometriosis and Chronic Pelvic Pain. Front Syst Neurosci. 2020;14:593581. https:// doi. org/ 10. 3389/ fnsys. 2020. 593581. 58. Halicka M, Vittersø AD, Proulx MJ, Bultitude JH. Neuropsychological Changes in Complex Regional Pain Syndrome (CRPS). Behav Neurol. 2020;2020(14):4561831. https:// doi. org/ 10. 1155/ 2020/ 45618 31. 59. Gariépy G, Honkaniemi H, Quesnel‑Vallée A. Social support and protec‑ tion from depression: systematic review of current findings in Western countries. Br J Psychiatry. 2016;209(4):284–93. https:// doi. org/ 10. 1192/ bjp. bp. 115. 169094. 60. Bedaso A, Adams J, Peng W, Sibbritt D. The relationship between social support and mental health problems during pregnancy: a systematic review and meta‑analysis. Reprod Health. 2021;18(1):162. https:// doi. org/ 10. 1186/ s12978‑ 021‑ 01209‑5. 61. Earle JR, Smith MH, Harris CT, Longino CF Jr. Women, marital status, and symptoms of depression in a midlife national sample. J Women Aging. 1998;10(1):41–57. https:// doi. org/ 10. 1300/ j074v 10n01_ 04. 62. Rooney KL, Domar AD. The relationship between stress and infertility. Dialogues Clin Neurosci. 2018;20(1):41–7. https:// doi. org/ 10. 31887/ DCNS. 2018. 20.1/ klroo ney. 63. Facchin F, Barbara G, Saita E, Erzegovesi S, Martoni RM, Vercellini P . Personality in women with endometriosis: temperament and character dimensions and pelvic pain. Hum Reprod. 2016;31(7):1515–21. https:// doi. org/ 10. 1093/ humrep/ dew108. 64. Grundström H, Larsson B, Arendt‑Nielsen L, Gerdle B, Kjølhede P . Pain catastrophizing is associated with pain thresholds for heat, cold and pres‑ sure in women with chronic pelvic pain. Scand J Pain. 2020;20(3):635–46. https:// doi. org/ 10. 1515/ sjpain‑ 2020‑ 0015. 65. Zarbo C, Brugnera A, Frigerio L, Malandrino C, Rabboni M, Bondi E, Com‑ pare A. Behavioral, cognitive, and emotional coping strategies of women with endometriosis: a critical narrative review. Arch Womens Ment Health. 2018;21(1):1–13. https:// doi. org/ 10. 1007/ s00737‑ 017‑ 0779‑9. 66. Yosef A, Allaire C, Williams C, Ahmed AG, Al‑Hussaini T, Abdellah MS, Wong F, Lisonkova S, Yong PJ. Multifactorial contributors to the severity of chronic pelvic pain in women. Am J Obstet Gynecol. 2016;215(6):760. e1‑760.e14. https:// doi. org/ 10. 1016/j. ajog. 2016. 07. 023. 67. Hemmert R, Schliep KC, Willis S, Peterson CM, Louis GB, Allen‑Brady K, Simonsen SE, Stanford JB, Byun J, Smith KR. Modifiable life style factors and risk for incident endometriosis. Paediatr Perinat Epidemiol. 2019;33(1):19–25. https:// doi. org/ 10. 1111/ ppe. 12516. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations.