Perceived cognitive functioning difficulties in individuals living with endometriosis

Abstract

Difficulties in cognitive functioning (e.g., memory, attention) are common in chronic conditions characterized by physical pain, fatigue and depression. Yet investigations in endometriosis are lacking. We aimed to assess: (1) perceived cognitive functioning, (2) the association of cognitive functioning with fatigue, pain and depressive symptoms, and (3) whether endometriosis treatments moderated these relationships. Participants (n = 1239) with diagnosed endometriosis completed an online survey assessing perceived cognitive functioning [Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog)], pain, fatigue and depression. FACT-Cog scores indicated cognitive impairments in 80% of participants. Hierarchical regression analyses demonstrated that greater pain, fatigue, and depressive symptoms were associated with poorer perceived cognitive functioning. Moderation analyses indicated that taking hormonal treatments or pain medications diminished the adverse effects of depression, but exacerbated the adverse effects of pain, on cognitive functioning. The extensive perceived cognitive difficulties evident in this sample suggests that supportive interventions to enhance cognitive functioning may be warranted.

Introduction

Endometriosis is a chronic, inflammatory condition characterized by chronic pelvic pain where tissue similar to the lining of the uterus grows in other parts of the body (As-Sanie et al., 2019; Rowlands et al., 2021). Common comorbidities (e.g. irritable bowel syndrome, migraines) (As-Sanie et al., 2019) may be linked to central sensitization, where the central nervous system becomes hypersensitive, leading to pain signals being amplified (Maulitz et al., 2022). With typical symptoms of chronic pelvic and abdominal pain, dyspareunia (painful sexual intercourse), dysmenorrhea (menstrual cramps), and fatigue (As-Sanie et al., 2019), it is unsurprising that quality of life is adversely impacted (Wang et al., 2021). Endometriosis symptoms have been linked with fatigue, sleep disruption (Facchin et al., 2021), impaired sexual relations, social isolation (As-Sanie et al., 2019; Wang et al., 2021) and psychological distress in the form of depressive symptoms and anxiety disorders (Sullivan-Myers et al., 2021; Wang et al., 2021).

Despite this high symptom burden, the psychosocial impacts of endometriosis are poorly understood (As-Sanie et al., 2019). Little is known about potential adverse impacts on cognitive functioning [i.e. neuropsychological processes such as information processing, attention, problem solving, and executive functioning (i.e. the ability to plan, remember instructions and multitask)] (Zhang et al., 2021). Limited qualitative data suggest difficulties relating to endometriosis-related physical fatigue, impacting on the ability to attend and think clearly (DiBenedetti et al., 2020), including at school (Moradi et al., 2014). Preliminary neuroimaging studies suggest the formation of an “endometriosis brain” where key areas of the brain associated with cognition may be impacted (Maulitz et al., 2022).

Pain and fatigue in endometriosis have also been associated with impaired social, school and work functioning (As-Sanie et al., 2019; Wang et al., 2021). Cognitive functioning difficulties may underlie these impairments in social, academic and work functioning. Clearly, quantitative investigations to identify and characterize potential cognitive functioning difficulties in this population are warranted; this study aims to address this gap in the evidence base.

In chronic conditions, pain, fatigue and cognitive functioning difficulties are linked. For example, individuals with chronic pain conditions such as fibromyalgia and chronic musculoskeletal pain, report a high incidence of cognitive functioning deficits when measured using objective (neuropsychological) testing (Zhang et al., 2021). In addition, these cognitive deficits are reported by individuals living with chronic pain in subjective assessments (i.e. perceived cognitive functioning difficulties) (Baker et al., 2018). These subjective reports of cognitive functioning provide a rich understanding of the lived experience of individuals and can elucidate the psychosocial aspects of cognitive deficits and their impact on quality of life. Subjective cognitive functioning assessment also has the advantage of facilitating wide-scale assessment, rather than time- and cost-intensive objective testing that is conducted one-on-one (Von Ah and Tallman, 2015; Pembroke et al., 2024b).

A strong link between fatigue and cognitive difficulties has been identified as assessed by objective and subjective measures in other fatigue-related conditions, including in chronic fatigue syndrome (Ocon, 2013) and breast cancer survivors (Von Ah and Tallman, 2015). Pain and fatigue may impair cognitive functioning by diminishing attentional control, thus disrupting information processing and later storage, leading to difficulties in memory and recall (Dick and Rashiq, 2007). Additionally, in multiple sclerosis, a disease characterized by cognitive dysfunction (due to brain lesions and atrophy), common symptoms of pain, fatigue and depressive symptoms have been linked to subjective cognitive difficulties including on a temporal daily basis (Kratz et al., 2017; Kinsinger et al., 2010). Furthermore, disturbances to sleep are linked to development of mild cognitive impairment (Hu et al., 2017) and cognitive decline in multiple sclerosis (Hughes et al., 2018). Disturbances in sleep have been identified as being associated with endometriosis and are linked to symptoms of physical fatigue (Facchin et al., 2021).

Additionally, depression, also a commonly experienced psychosocial sequelae of endometriosis, is another factor associated with diminished cognitive functioning across multiple objectively assessed cognitive domains (e.g. memory, attention and executive function) in those not affected by chronic pain, (Douglas et al., 2018), as well as through subjective cognitive functioning assessment (Kim et al., 2016) and reflected in chronic pain populations (James and Ferguson, 2020). Depressive symptoms may develop in individuals as a consequence of experiencing chronic pain, with those experiencing endometriosis-related pelvic pain reporting greater depressive symptoms, compared to those without pelvic pain (Gambadauro et al., 2019).

As highlighted in several chronic conditions, multiple factors (i.e. pain, fatigue, sleep disruption, depression) are associated with cognitive functioning, and these relationships are complex and bidirectional (Facchin et al., 2021; Valentine et al., 2021). Underlying these relationships are several shared neurobiological mechanisms, including: neuroinflammation, neuroanatomical changes, HPA axis dysregulation and monoamine dysregulation (Chitnis et al., 2022).

Given the common symptom profile of pain- (e.g. fibromyalgia, chronic musculoskeletal pain) and fatigue- (e.g. chronic fatigue syndrome) related conditions with endometriosis (i.e. chronic pain, fatigue, psychosocial impacts)(As-Sanie et al., 2019), it is likely that similar cognitive functioning difficulties may be experienced by those living with endometriosis; yet, no studies have quantitatively assessed these difficulties.

In addition, the link between these key psychosocial factors (i.e. pain, fatigue and depression) and cognitive functioning may be strengthened by the use of hormonal treatments, a commonly-used approach to slow the growth of endometrial lesions and manage endometriosis-related pain (Ferrero et al., 2024). Hormonal treatments range from contraceptive pills through to stronger endocrine medications that function by essentially creating a medical menopause (Ferrero et al., 2024). Although oral contraceptives are widely used, they have been linked with deficits in cognitive functioning (Gurvich et al., 2023). Moreover, unwanted side effects of hormonal treatments, such as headaches and mood changes (e.g. depression) have also been linked with cognitive deficits (Begasse de Dhaem and Robbins, 2022; Douglas et al., 2018). Critically, endocrine medications [e.g., gonadotropin-releasing hormonal agonists (GnRHas), aromatase inhibitors], are associated with even greater side-effects that are known to impact on cognitive functioning including memory loss, and difficulties with concentration (Craig et al., 2007; Grigorova et al., 2006).

Furthermore, use of pain medications to directly treat symptoms of physical pain is common in individuals with endometriosis, with Non-steroidal anti-inflammatory drugs (NSAIDs) most commonly taken, and as a second-line treatment, opioid medications (Chiuve et al., 2021). Although opioids are not a recommended treatment for endometriosis, more than half of individuals with endometriosis are likely to have been prescribed them within one year of diagnosis (As-Sanie et al., 2021), which is concerning given their link with a range of adverse side-effects, including impairments to cognitive functioning (Akhurst et al., 2021). Additionally, it is common for individuals with endometriosis to undergo surgery, particularly laparoscopy to remove lesions, and less-commonly, hysterectomy (Ferrero et al., 2024). These surgeries involve use of anaesthesia, which is linked with temporary deficits in cognitive functioning (Belrose and Noppens, 2019). No studies to date have explored the possible adverse effects of different treatments for endometriosis on cognitive functioning.

In summary, since individuals with endometriosis experience many of the symptoms (e.g. chronic pain, fatigue, depression) of other chronic pain-and fatigue-related conditions (As-Sanie et al., 2019), they may also experience similar cognitive functioning difficulties. The primary aim of this study was to build on the preliminary qualitative reports suggestive of cognitive functioning deficits in endometriosis (DiBenedetti et al., 2020; Moradi et al., 2014), by quantitatively assessing perceived cognitive functioning (Wagner et al., 2009). Further, we aimed to delineate the association between pain, fatigue and depressive symptoms with perceived cognitive difficulties in endometriosis and we explored the potential moderating effect of different types of treatments on these associations.

Methods

Participants

Inclusion criteria for this study were: (1) self-reporting having a prior medical diagnosis of endometriosis; (2) being an Australian resident; (3) English-language proficiency; (4) being at least 18 years old; and (5) having internet access. An exclusion criterion was current pregnancy, since there is evidence that pregnancy may adversely impact cognitive functioning (Davies et al., 2018). Nine individuals were subsequently excluded from the study on the basis of self-reporting being pregnant.

Participants (N = 1239) were invited to the study via the social media platforms of two endometriosis online community organizations (Endometriosis Australia and Endogram), and through the institutional undergraduate Psychology research participation pool in return for partial course credit between May-July 2021. Initially, 2364 individuals accessed the study site, and were assessed for eligibility. As displayed in Figure 1, in total 1239 individuals meeting eligibility criteria gave online consent. Following online informed consent, participants completed an online survey in REDCap assessing cognitive functioning, pain, fatigue, depression, and demographic and medical information. Data for this study were collected as the baseline assessment point of a larger, longitudinal study (Pehlivan et al., 2022).

Figure 1.

Flowchart of participant recruitment.

Note. FACT-Cog = The Functional Assessment of Cancer Therapy–Cognitive Function version 3; SF-MPQ-2-T = McGill Pain Questionnaire Short-form 2 Total score; PROMIS-Fatigue = PROMIS Fatigue Short-Form 6a; DASS-D = Depression Anxiety Stress Scale-21 Depression Subscale.

A power analysis using G*Power indicated a minimum sample size of 127 was required to detect a small-to-medium effect size in perceived cognitive functioning [based on prior research in another health context that measured associations between pain, fatigue and cognition using the FACT-Cog (Nicol et al., 2019)], with power of at least 0.80 and a .05 significance level. This research was conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Ethics approval was obtained from the institutional Human Research Ethics Committee (approval number: 52021952428132). The study was also registered on the Open Science Framework (https://osf.io/5xeck). Study method and results are reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and Statement for cross-sectional studies (Von Elm et al., 2007; O’Brien et al., 2014).

Measures

Perceived cognitive functioning

The Functional Assessment of Cancer Therapy–Cognitive Function version 3 (FACT-Cog) is a self-report measure of perceived cognitive functioning, assessing mental acuity, memory (verbal and nonverbal), verbal fluency and attention (Wagner et al., 2009) across four subscales: Perceived cognitive impairments (PCI; scores from 0 to 72); Perceived cognitive abilities (PCA; scores from 0-28); Comments from others (CFO; scores from 0 to 16); and Impact of perceived cognitive impairments on quality of life (QOL; scores from 0 to 16). Prior Australian research has demonstrated the validity of the FACT-Cog with non-cancer populations, including a population from the general public who were all adult females (Koch et al., 2023), and in older adults and students (Costa et al., 2018). In the current sample, a maximum likelihood exploratory factor analysis using a varimax rotation yielded the expected four factor structure of the FACT-Cog (Wagner et al., 2009).

Participants rated statements relating to their cognitive abilities (PCI e.g., “My thinking has been slow”; PCA e.g. “I have been able to concentrate”; CFO e.g. “Other people have told me I seemed to have trouble thinking clearly” and QOL e.g. “These problems have interfered with my ability to work”) over the past month on 5-point Likert-type scales: PCI and CFO; [0 “never” to 4 “several times a day”] and PCA and QOL; [0 ‘not at all’ to 4 ‘very much’], with higher summed scores indicating greater cognitive functioning (Wagner et al., 2009). In the original version of this measure, participants rate their cognition over the past 7 days and this has been modified for the endometriosis population to 1 month due to the cyclical nature of endometriosis (Bourdel et al., 2014).

The FACT-Cog has demonstrated reliability and validity in cancer and non-cancer patient samples (Costa et al., 2018; Wagner et al., 2009). In the current study, internal consistency was high: PCA (α = 0.89), QOL (α = 0.94), CFO (α = 0.89) and PCI (α = 0.96), consistent with prior research (Cheung et al., 2013; Wagner et al., 2009). A cut-off score for cognitive impairment was determined by previous research, with scores less than 54 on the PCI scale indicating cognitive impairment in participants (Van Dyk et al., 2019).

Pain

Perceived pain was assessed with the Short Form McGill Pain Questionnaire 2 (SF-MPQ-2), a 22-item self-report measure assessing continuous, intermittent, neuropathic and affective domains of pain (Dworkin et al., 2009). Participants rate the intensity of 22 descriptor words regarding their pain (e.g. “throbbing”) in the past month on a 10-point scale (0 “none” to 10 “worst possible”). Higher total mean scores (SF-MPQ-2-T) for the 22 descriptors indicate greater pain intensity (Dworkin et al., 2009). The SF-MPQ-2 has demonstrated reliability (α = 0.96) and validity (Lovejoy et al., 2012) and has been frequently utilized in endometriosis populations, as highlighted in a systematic review of pain assessment in endometriosis, as it allows participants to define their own pain using the numerous descriptor words (Bourdel et al., 2014). In the current study internal consistency was high (α = 0.93).

Fatigue

The 6-item Patient Reported Outcome Measurement Information System (PROMIS) Fatigue-Short form 6a (PROMIS Fatigue SF-6a) (Bingham et al., 2019) measured physical fatigue (this measure does not capture cognitive aspects of fatigue). Participants rate items relating to their levels of fatigue (e.g. “I feel fatigued”) in the past month (1 “not at all” to 5 “very much”). Total scores range from 6-30, with higher scores indicating greater fatigue (PROMIS, 2019). This measure has demonstrated reliability (α = 0.93) and validity in the endometriosis context (Pokrzywinski et al., 2020). In the current study internal consistency was high (α = 0.93).

Depressive symptoms

The 7-item Depression subscale of the Depression, Anxiety and Stress Scales (DASS-21) was used to measure depressive symptoms (Lovibond and Lovibond, 1995). Participants rate statements relating to depression (e.g., “I couldn’t seem to experience any positive feeling at all”) on a Likert-type scale (0 “did not apply to me at all” to 3 “applied to me very much or all of the time”) over the past month. Total scores range from 0 to 21, with higher scores indicating moderate (i.e. ranging from 7 to 10) or severe (11+) depressive symptoms. The DASS-21 has demonstrated reliability and validity (Bibi et al., 2020), including in the endometriosis context (Sullivan-Myers et al., 2021; Pehlivan et al., 2022). In the current study, the internal consistency of the scale was high (α = 0.92).

Potential covariates

Demographic and medical history

Demographic (i.e. age, education level, country of residence, employment status, Australian Indigenous status, relationship status) information was collected, as well as medical history (i.e. symptoms experienced, endometriosis treatments received in the past 12 months, method of diagnosis, diagnostic delay). Self-rated endometriosis severity was assessed via a single Likert-type scale item (4-point Likert scale: 1 “no symptoms” to 4 “severe”), that has been used in prior endometriosis research (Pehlivan et al., 2022; Sullivan-Myers et al., 2021).

Statistical analysis

All quantitative analyses were undertaken using STATA version 17. Descriptive statistics were generated to characterize the sample and identify perceived cognitive difficulties, fatigue, pain and depressive symptoms. Scores on cognitive functioning, pain, fatigue and depression scales were only included in analyses if participants completed at least 70% of items in each scale. Consequently, the number of participants included in the analysis of each scale differs (see Figure 1).

Bivariate analyses were conducted (Spearman’s rho or Kruskal-Wallis H tests due to non-normal distributions) to identify associations between cognitive functioning and demographic and medical factors, and potential covariates for the main analyses. To assess the association of pain, fatigue and depression with each of the four subscales measuring perceived cognitive functioning, four separate hierarchical linear regression analyses were conducted, with identified covariates added in Step 1. Hierarchical regression was utilized to determine the extent to which the different groups of variables accounted for variance in cognitive functioning, whilst controlling for other variables. To explore the potential moderating effects of different types of therapies (i.e. surgery, pain medication, and hormonal treatment) on the relationship of pain, fatigue and depression on cognitive functioning, interaction terms were added to each of the hierarchical regression analyses, and predictor variables were centred. When interaction terms were non-significant, they were removed for the reporting of final models.

Results

Sample characteristics are displayed in Table 1, along with analyses investigating bivariate associations of demographic and medical variables with each of the four FACT-Cog subscales. Older age, greater perceived endometriosis severity, a greater number of self-reported endometriosis symptoms and treatments received, lower education level and being unemployed (as opposed to being employed) were associated with worse cognitive functioning for all FACT-Cog subscales, as was the use of hormonal medication for PCI, QOL and PCA subscales and pain medication for the PCI, QOL and PCA subscales.

Table 1.

Sample characteristics.

Variables	M(SD) or n (%)	Relationship with cognitive functioning
		PCI	QOL	CFO	PCA
		rs or H	rs or H	rs or H	rs or H
Age (years) † -M (SD) (n = 1238)	29.80(7.32)	0.11**	0.16**	0.12**	0.10**
Relationship status ‡ -n (%)		2.28	1.02	.25	.27
Partnered	963 (77.72)
Not partnered	276 (22.28)
Australian Aboriginal or Torres Strait Islander ‡ -n(%)		2.72	6.35*	2.14	1.19
Indigenous	37 (3.13)
Non-Indigenous	1146 (96.87)
Infertility ‡ -n (%)		.11	1.12	.11	.40
Infertile	99 (11.74)
Not infertile	744 (88.26)
Location ‡ -n (%)		.37	.87	.25	.49
Australia/NZ	1059 (90.67)
Rest of World	109 (9.33)
Employment ‡ -n (%)		19.51**	24.91**	20.51**	15.92**
Full time	628 (53.04)
Part-time	264 (22.30)
Student	115 (9.71)
Unemployed	176 (14.86)
Education ‡ - n (%)		24.26**	18.70**	32.10**	10.94*
High school or less	297 (25.11)
TAFE/Vocational	259 (21.89)
Undergraduate degree	417 (35.35)
Postgraduate degree	210 (17.75)
Endometriosis severity † -M(SD) (n = 1164)	3.26 (.68)	-.15**	-.17**	-.15**	-.09**
No. of symptoms † - M(SD) (n = 1239)	6.63 (2.40)	-.26**	-.22**	-.20**	-.19**
No. of treatments † -M (SD) (n = 1239)	1.82 (1.03)	-.12**	-.15**	-.10**	-.12**
Treatments ‡ -n (%)
Surgery §	573 (46.25)	.26	2.53	3.95	.65
Hormonal medication §	628 (50.69)	4.37*	7.62**	1.91	4.18*
Pain medication §	926 (74.74)	12.89**	11.27**	2.83	9.27**
Alternative therapy §	36 (2.91)	2.52	.79	2.38	1.47
Manual therapy §	56 (4.52)	7.13**	4.09*	1.45	3.12

PCI: Perceived cognitive impairment; QOL: Impact of perceived cognitive impairments on quality of life; CFO: Comments from others; PCA: Perceived cognitive abilities; DASS-D: Depression Anxiety Stress Scale-21 Depression Subscale; rs: Spearman’s rank correlation coefficient; H: Kruskal-Wallis H statistic. “Surgery” typically refers to laparoscopy; “Pain medication” refers to medications to directly treat symptoms of physical pain, including NSAIDs; “Hormonal medication” refers to medications containing oestrogen and/or progestin; “Alternative therapy” refers to alternative treatments utilized (e.g. acupuncture, herbal, naturopathy, Chinese medicine, homeopathic); “Manual therapy” refers to physiotherapy, use of a TENS machine, osteopathic, chiropractic therapies.

^†Spearman’s rank correlation coefficient was used as the assumption of normality was violated.

^‡Kruskal-Wallis H test was used as the assumption of normality was violated.

^§Variables are coded 0 = No, 1 = Yes.

^*p < 0.05, two-tailed. **p < 0.01, two-tailed.

Descriptive statistics and bivariate associations (Spearman’s correlations) for cognitive functioning, fatigue, pain and depressive symptoms are displayed in Table 2. The mean score of the PCI subscale indicated that the sample was classified as being cognitively impaired (i.e. PCI scores <54), with 80.11% of participants scoring above the threshold for cognitive impairment (Van Dyk et al., 2019). Mean scores on pain were relatively high and exceeded scores of a previously reported chronic pain population (Lovejoy et al., 2012). Fatigue levels were greater than that previously reported for endometriosis samples (Pokrzywinski et al., 2020) and the US general population (PROMIS, 2019). Mean scores on the DASS-D indicated 56% of the sample were experiencing at least moderately-severe depressive symptoms (Lovibond and Lovibond, 1995).

Table 2.

Spearman’s correlations between cognitive functioning, pain, fatigue, and depressive symptoms.

Variables	1	2	3	4	5	6	7
1.SF-MPQ-2-T	–
2. PROMIS-Fatigue	.33**	–
3. DASS-D	.38**	.40**	–
4. PCI	−.40**	−.45**	−.48**	–
5. QOL	−.37**	−.47**	−.60**	.65**	–
6. CFO	.65**	−.30**	−.40**	.65**	.51**	–
7. PCA	.66**	−.36**	−.39**	.66**	.51**	.50**	–
M	4.85	25.18	8.28	37.91	7.75	12.92	12.56
SD	2.09	4.62	5.62	17.83	4.98	3.76	5.97
n	1078	1003	958	1051	1005	1038	1014

PCI: Perceived cognitive impairment; QOL: Impact of Perceived cognitive impairments on quality of life; CFO: comments from others; PCA: Perceived cognitive abilities; PROMIS-Fatigue: PROMIS Fatigue Short-Form 6a; SF-MPQ-2-T: McGill Pain Questionnaire Short-form 2 Total score.

^**Correlation is significant at the 0.01 level (two-tailed).

For all FACT-Cog subscales, cognitive functioning was significantly associated with pain, fatigue, and depression, controlling for relevant covariates. Full models including only significant interactions are displayed in Table 3 and full models with all interactions are available in the Supplemental File.

Table 3.

Hierarchical linear regression analyses for cognitive functioning measures.

Outcome	Variable	B (SE)	b 95% CI [LL,UL]	β	t	p	ΔR 2	F
PCI	Step 1						–	90.78**
	Covariates
	Age	0.18 (0.08)	0.14, 0.34	0.07	20.12*	0.03
	Employment status
	Part time	0.34 (10.38)	−20.36, 30.05	0.01	25	0.81
	Student	10.40 (20.04)	−20.60, 50.40	0.02	0.69	0.50
	Not employed	−40.99 (10.65)	−80.23, −10.75	−0.10	−30.02**	0.003
	Education level
	Undergraduate	0.24 (10.63)	−20.94, 30.43	0.01	0.15	0.89
	Postgraduate	30.54 (10.49)	0.63, 60.45	0.10	20.38*	0.02
	TAFE	50.08 (10.81)	10.53, 80.64	0.11	20.80**	0.005
	Endo. Severity	−10.84 (0.87)	−30.55, −0.13	−0.07	−20.12*	0.04
	No. of Symptoms	−20.13 (0.34)	−20.79, −10.46	−0.21	−60.26**	<0.001
	No. of treatments	−0.54 (10.03)	−20.55, 10.48	−0.03	−0.52	0.60
	Pain medication	−20.70 (10.69)	−60.01, 60.11	−0.06	−10.60	0.11
	Manual treatment	−20.86 (20.83)	−80.40, 20.68	−0.04	−10.01	0.31
	Hormonal treatment	0.03 (10.58)	−30.07, 30.31	<0.001	0.02	0.10
	Step 2						0.24	310.90**
	Psychosocial variables
	SF-MPQ-2-T	−10.26 (0.28)	−10.83, −0.71	−0.15	−40.45**	<0.001
	DASS-D	−0.95 (0.10)	−10.14, −0.76	−0.30	−90.85**	<0.001
	PROMIS-Fatigue	−0.99 (0.12)	−10.22, −0.76	−0.26	−80.44**	<0.001
	Step 3						<0.001	30.38*
	Interaction term
	Hormonal treatment x DASS−D	0.35 (0.17)	0.01, 0.68	0.12	20.04*	0.04
PCA	Step 1						−	50.92**
	Covariates
	Age	0.09 (0.03)	0.03, 0.14	0.10	20.96**	0.003
	Employment status
	Part time	0.22 (0.47)	−0.71, 10.15	0.02	0.51	0.61
	Student	0.47 (0.70)	−0.91, 10.85	0.02	0.70	0.48
	Not employed	−10.94 (0.57)	−30.05, −0.82	−0.11	−30.37**	0.001
	Education level
	Undergraduate	0.43 (0.56)	−0.67, 10.53	0.03	0.76	0.45
	Postgraduate	0.84 (0.51)	−0.17, 10.84	0.07	10.66	0.10
	TAFE	0.87 (0.62)	−0.35, 20.10	0.06	10.43	0.15
	Endo. Severity	0.01 (0.30)	−0.59, 0.59	<0.001	−0.01	0.99
	No. of symptoms	−0.52 (0.12)	−0.75, −0.29	−0.15	−40.43**	<0.001
	No. of treatments	−0.29 (0.24)	−0.91, 0.32	−0.05	−0.45	0.65
	Pain medication	−0.93 (0.55)	−20.04, 0.20	−0.06	−10.74	0.08
	Hormonal treatment	0.07 (0.52)	−10.00, 10.03	0.02	−0.22	0.83
	Step 2						0.15	170.29**
	Key variables
	SF-MPQ-2-T	−0.30 (0.10)	−0.49, −0.10	−0.10	−20.89**	0.004
	DASS-D	−0.23 (0.04)	−0.30, −0.15	−0.21	−60.34**	<0.001
	PROMIS-Fatigue	−0.30 (0.04)	−0.40, −0.26	0.25	−70.78**	<0.001
	Step 3						<0.001	160.73**
	Interaction term
	Hormonal treatment x DASS-D	0.15 (0.06)	0.03, 0.28	0.16	20.48*	0.01
CFO	Step 1						−	70.79**
	Covariates
	Age	0.04 (0.02)	0.02, 0.05	0.07	20.17*	0.03
	Employment status
	Part time	−0.41 (0.29)	−0.98, 0.16	−0.05	−10.39	0.16
	Student	−0.11 (0.43)	−0.97, 0.73	−0.01	−0.26	0.79
	Not employed	−10.44 (0.35)	−20.13, −0.76	−0.14	−40.11**	<0.001
	Education level
	Undergraduate	−0.12 (0.34)	−0.790. 0.56	−0.01	−0.35	0.73
	Postgraduate	0.97 (0.31)	0.34, 10.57	0.13	30.05**	0.002
	TAFE	10.18 (0.38)	0.42, 10.92	0.12	30.06**	0.002
	Endo. Severity	−0.49 (0.18)	−0.85, −0.12	−0.09	−20.64**	0.008
	No. of Symptoms	−0.25 (0.07)	−0.39, −0.11	−0.12	−30.50**	<0.001
	No. of treatments	−0.19 (0.13)	−0.58, 0.07	−0.05	−10.08	0.28
	Pain medication	0.02 (0.36)	−0.68, 0.72	0.01	0.05	0.10
	Manual therapy	−0.18 (0.60)	−10.35, 0.99	−0.01	−0.30	0.76
	Hormonal treatment	0.17 (0.28)	−0.58, 0.07	0.02	0.60	0.53
	Step 2						0.14	180.53**
	Key variables
	SF-MPQ-2-T	−0.35 (0.06)	−0.47, −0.22	−0.20	−50.48**	<0.001
	DASS-D	−0.17 (0.02)	−0.21, −0.13	−0.26	−70.89**	<0.001
	PROMIS-Fatigue	−0.08 (0.03)	−0.13, −0.02	−0.10	−20.90**	0.004
	Step 3						<0.001	170.75**
	Interaction term
	Pain Medication x SF-MPQ-2-T	−0.25 (0.12)	−0.49, −0.01	−0.12	−20.08*	0.04
QOL	Step 1						−	90.62**
	Covariates
	Age	0.09 (0.02)	0.04, 0.14	0.13	30.82**	<0.001
	Employment status
	Part time	0.24 (0.39)	−0.52, 10.00	0.02	0.63	0.54
	Student	0.01 (0.57)	−10.11, 10.13	0.005	0.02	0.10
	Not employed	−10.71 (0.46)	−20.62, −0.81	−0.12	−30.71**	<0.001
	Education level
	Undergraduate	0.77 (0.46)	−0.13, 10.66	0.06	10.68	0.10
	Postgraduate	10.02 (0.42)	20,10.84	0.10	20.45*	0.02
	TAFE	10.12 (0.51)	20,10.84	0.09	20.18*	0.02
	Endo. Severity	−0.75 (0.24)	−10.22, −0.27	−0.10	−30.06**	0.002
	No. of symptoms	−0.43 (0.09)	−0.62, −0.25	−0.15	−40.54**	<0.001
	No. of treatments	−0.42 (0.21)	−10.09, 0.05	−0.08	10.80	0.07
	Pain medication	−0.36 (0.45)	−10.21, 0.65	−0.03	−0.60	0.50
	Manual treatment	−0.07 (0.75)	−10.49, 10.62	−0.01	0.08	0.93
	Indigenous status	20.00 (0.89)	0.27, 30.71	0.07	20.27*	0.02
	Hormonal treatment	0.26 (0.07)	−0.64, 10.09	−0.11	−0.51	0.61
	Step 2						0.30	410.28**
	Key variables
	SF-MPQ-2-T	−0.26 (0.08)	−0.40, −0.11	−0.23	−30.43**	0.001
	DASS-D	−0.38 (0.20)	−0.43, −0.32	−0.43	−150.02**	<0.001
	PROMIS-Fatigue	−0.24 (0.03)	−0.10, −0.18	0.04	−70.84**	<0.001
	Step 3						<0.001	390.32**
	Interaction term
	Hormonal Treatment x SF-MPQ-2-T	−0.23 (0.12)	−0.47, −0.004	−0.14	−10.96*	0.05

PCI: Perceived cognitive impairments; QOL: Quality of life; CFO: Comments from Others; PCA: Perceived cognitive abilities; Endo. Severity: endometriosis severity; DASS-D: Depression Anxiety Stress Scale-21 Depression Subscale; PROMIS-Fatigue: PROMIS Fatigue Short-Form 6; SF-MPQ-2-T: McGill Pain Questionnaire Short-form 2 total score, UL: upper limit, LL: lower limit.

^*p < 0.05. **p < 0.01.

A significant interaction (hormonal treatment x depression) was evident for the PCI subscale, suggesting a protective effect such that at greater levels of depressive symptoms, individuals on hormonal treatment reported comparatively fewer adverse impacts on PCI (see Figure 2). For those experiencing low levels of depressive symptoms, PCI scores were relatively low, irrespective of whether they were taking a hormonal treatment or not. Neither pain nor fatigue demonstrated significant hormone treatment interaction effects.

Figure 2.

Interaction plot of hormonal treatment by depressive symptoms for PCI.

For the PCA subscale, the hormonal treatment x depression interaction was significant such that at greater levels of depressive symptoms, individuals on a hormonal treatment reported comparatively fewer adverse impacts on PCA. Whereas at low levels of depression, the effects of being on a hormonal treatment did not impact PCA scores (see Figure 3). Neither pain nor fatigue demonstrated significant interaction effects.

Figure 3.

Interaction plot of hormonal treatment by depressive symptoms for PCA.

For the QOL subscale, there was a significant interaction of hormonal treatment x pain, such that at higher levels of pain, being on a hormonal treatment exacerbates the adverse impacts of pain on cognitive functioning, whereas for those reporting no pain, being on a hormonal treatment did not impact perceived cognitive functioning (See Figure 4).

Figure 4.

Interaction plot of hormonal treatment by pain for QOL.

For the CFO subscale, was a significant interaction of pain medication x pain, such that at higher levels of pain, being on a hormonal treatment exacerbates the adverse impacts of pain on cognitive functioning, whereas for those reporting no pain, being on a hormonal treatment did not impact perceived cognitive functioning (See Figure 5)

Figure 5.

Interaction plot of pain medication by pain for CFO.

There were no significant interactions for surgery.

Discussion

This study provides novel findings about perceived cognitive functioning in individuals living with endometriosis, using quantitative investigation techniques to explore cognition. Individuals with endometriosis reported difficulties with cognitive functioning across multiple domains, with most participants reporting average cognitive functioning scores consistent with a clinically significant cognitive impairment (Van Dyk et al., 2019). Further, compared to prior samples of cancer patients, who commonly report brain fog (Kiang et al., 2016), this sample of individuals with endometriosis fared worse in perceived cognitive functioning.

The high percentage (80%) of those with scores on the FACT-Cog PCI (indicative of clinically significant cognitive impairment) is highly concerning given the relatively young age of this sample (<30 years), with younger adulthood being an important life phase for the formation of social and romantic relationships, as well as establishing a career and becoming more autonomous (Allott et al., 2016). Cognitive impairments may further complicate achievements in these important life milestones, with cognitive impairments in other populations (e.g. young adults with cancer-related cognitive impairment) being linked to reduced functioning in areas including work/school, emotional functioning and social functioning (Sharma and Brunet, 2023).

It is likely that the high level of workplace absenteeism and dropout that has been attributed to the difficulties of living with endometriosis (Armour et al., 2022) may reflect previously undocumented difficulties with cognitive functioning. If this is the case, interventions such as cognitive rehabilitation programs, which encompass both cognitive training and techniques to improve emotional wellbeing, may be beneficial (Nakamura et al., 2024; Pembroke et al., 2024a). Further, for a younger adult population that is technologically savvy, highly accessible online interventions designed to enhance cognitive functioning may be particularly well suited (Vergani et al., 2019).

Greater pain than previously reported in a chronic pain population (Lovejoy et al., 2012) was reported in this sample, as were high levels of fatigue that exceeded prior reports in endometriosis (Pokrzywinski et al., 2020) and chronic pelvic pain (Fenton et al., 2011), and were similar to that reported in a CFS sample (Yang et al., 2019). Fatigue may be explained by both the large number of symptoms being experienced as well as the high proportion of participants in this study who were using hormonal treatments, as this is a commonly-cited side effect (Ferrero et al., 2024). As predicted, pain and fatigue were significantly associated with poorer perceived cognitive functioning (Ocon, 2013; Zhang et al., 2021). Cognitive difficulties associated with pain and fatigue have previously been reported across a wide range of other chronic illness populations including CFS, chronic pain, and breast cancer (Von Ah and Tallman, 2015; Zhang et al., 2021; Kratz et al., 2017).

Consistent with prior research, individuals with endometriosis reported high levels of depressive symptoms (Wang et al., 2021) and these were strongly linked with cognitive functioning difficulties, as has been found in other chronic illness (James and Ferguson, 2020) and non-chronic illness populations (Douglas et al., 2018). This link between depression and cognitive functioning difficulties was highest for the domains of quality of life and perceived cognitive abilities. Depression may impact cognitive functioning in slowing down thinking, and impairing concentration, decision making and recall (Douglas et al., 2018).

Moreover, moderation analyses revealed a protective effect of the use of a hormonal treatment on the link between higher depressive symptoms and cognitive functioning difficulties in individuals who report high levels of depressive symptoms, in line with research finding a protective association between contraceptive use and depressive symptoms (Keyes et al., 2013; Young et al., 2007). However, it is unclear what the precise mechanism is that is driving this interaction effect, particularly due to the vast number of different hormonal treatments and measurement of depressive symptoms (De Wit et al., 2020) with some cohort studies indicating a link between oral contraceptive use and higher depressive symptoms (De Wit et al., 2020; Skovlund et al., 2016). Additionally, the use second-line hormonal treatments for endometriosis (e.g. GnRHa medications) is associated with side effects of depressive symptoms (Gallagher et al., 2018; Stenbæk et al., 2015). More research is needed to investigate the mechanisms underlying these relationships.

In contrast, the opposite effect was found for levels of pain, in that, for those using some form of hormonal treatment, these treatments appeared to exacerbate the relationship between pain and poorer cognitive functioning, for those reporting high levels of pain. This effect was paralleled in the use of pain medications, in that for individuals taking some form of pain medication, these medications appeared to also exacerbate the relationship between pain and poorer cognitive functioning, for those reporting high levels of pain. This suggests that participants taking either hormonal treatments or pain medications are not perceiving reductions in pain that are anticipated by taking these treatments, which is in contrast to findings indicating the efficacy of various hormonal treatments in reducing levels of pain in individuals with endometriosis, specifically; oral contraceptives, progestin-only therapies, and second-line treatments (e.g. GnRHa medications) (Ferrero et al., 2024). In contrast, there is mixed evidence concerning the efficacy of commonly taken NSAIDs (Ferrero et al., 2024) and although opioids may be effective for reducing short-term pain associated with surgery, they are not recommended for chronic pain management (Chiuve et al., 2021).

Additionally, the current sample reported to be taking a variety of different hormonal treatments, which makes it difficult to differentiate the individual effects of each hormonal treatment on levels of pain, and it was unknown which types of pain medications patients were taking. Further research is needed to further understand these relationships, and the effects of different forms of treatments should be teased apart.

These findings extend previous qualitative accounts of cognitive impairments (DiBenedetti et al., 2020; Moradi et al., 2014), in using a validated measure to assess perceived cognitive functioning and highlight a further psychosocial challenge for individuals living with endometriosis. The focus on perceived cognitive functioning captured the subjective experiences of these individuals; however, neuropsychological testing research is needed to objectively confirm these perceived deficits (Vardy et al., 2006). Nevertheless, prior research with breast cancer survivors demonstrated high correlations between scores on the FACT-Cog measure and objective cognitive measures, indicating that self-report measures are useful and valid measures of cognition (Von Ah and Tallman, 2015).

It was beyond the scope of this cross-sectional study to examine the directionality and underlying mechanisms in the link between pain, fatigue and depression with cognitive functioning, however, future research should investigate the role of attention (Moriarty and Finn, 2014). We recruited a large community sample primarily from online endometriosis consumer-organizations, which may have led to a self-selection bias, in that those with more severe endometriosis may have been more motivated to participate, and non-internet connected individuals were precluded (<1% of the Australian population) (De Graaff et al., 2013; Ramos-Echevarría et al., 2021). Further, the online nature of the study precluded verification using medical records of self-reported diagnosis. Additionally, all variables were measured using similar methods, which may have led to a “common method bias,” which may be overcome in future research through the use of longitudinal methods (Podsakoff et al., 2024). Furthermore, given that the time frame of the FACT-Cog was adjusted to capturing perceived cognitive functioning in the last month (in order to capture the cyclical nature of endometriosis (Bourdel et al., 2014)), future research should conduct further validation of this adjusted timeframe in the endometriosis population. Future research should also include a measure of sleep quality, given the growing literature demonstrating a link between sleep disturbance and cognitive impairments (Hu et al., 2017; Hughes et al., 2018).

Additionally, a measure of gender was not included in the current study, meaning that the experience of transgender men and non-binary people was not captured and these populations have reported distinct experiences relating to their endometriosis (Eder and Roomaney, 2024), as well as a lack of assessment of potential participant comorbidities, which may have influenced variables of interest. Although it was out of the scope of the survey design nature of the current study to include an objective measure of pain (e.g. quantitative sensory testing), future research could consider utilizing these types of measures, as they give an objective account of participants’ levels of pain and give insight into mechanisms underlying the experience of pain (Weaver et al., 2021). Finally, participants only reported on whether they had utilized hormonal treatments during the past 12 months, which may have not accurately captured the use of hormonal treatments at the time of the study completion.

In summary, this study provides novel findings regarding perceived cognitive functioning in individuals with endometriosis, demonstrating that individuals with endometriosis perceive significantly high levels of impairment, and highlighting a critical unmet support need for this population. Pain, fatigue and depressive symptoms were all linked with perceived cognitive difficulties in individuals living with endometriosis. Future research should examine the underlying mechanisms behind the relationship between cognitive functioning and pain, fatigue and symptoms of depression, as well as to identify potential targets for intervention.