FIT Teens RCT for juvenile fibromyalgia: Protocol adaptations in response to the COVID 19 pandemic.

Objective: To describe protocol adaptations to the Fibromyalgia Integrative Training for Teens (FIT Teens) randomized controlled trial in response to the COVID-19 pandemic. The overarching aims of the FIT Teens multi-site 3-arm comparative effectiveness trial are to assess whether a specialized neuromuscular exercise training intervention combined with cognitive-behavioral therapy (CBT) is superior to CBT alone or graded aerobic exercise alone. Design/methods: The trial was originally designed as an in-person, group-based treatment with assessments at baseline, mid- and post-treatment, and four follow-up time points. The original study design and methodology was maintained with specific modifications to screening, consenting, assessments, and group-based treatments to be delivered in remote (telehealth) format in response to COVID-19 restrictions. Results: Study enrollment was paused in March 2020 for five months to revise operations manuals, pilot remote treatment sessions for accuracy and fidelity, complete programming of REDCap assent/consent and assessment materials, train study staff for new procedures and obtain regulatory approvals. The trial was relaunched and has been successfully implemented in remote format since July 2020. Trial metrics thus far demonstrate a consistent rate of enrollment, strong attendance at remote treatment sessions, high retention rates and high treatment fidelity after protocol adaptations were implemented. Conclusions: Preliminary findings indicate that FIT Teens protocol adaptations from in-person to remote are feasible and allowed for sustained enrollment, retention, and treatment fidelity comparable to the in-person format. Methodologic and statistical considerations resulting from the adaptations are discussed as well as implications for interpretation of results upon completion of the trial.

Neural mechanisms that promote food consumption following sleep loss and social stress: an fMRI study in adolescent girls with overweight/obesity.

STUDY OBJECTIVES: Insufficient sleep and social stress are associated with weight gain and obesity development in adolescent girls. Functional magnetic resonance imaging (fMRI) research suggests that altered engagement of emotion-related neural networks may explain overeating when under stress. The purpose of this study is to explore the effects of acute sleep restriction on female adolescents' neural responding during social evaluative stress and their subsequent eating behavior. METHODS: Forty-two adolescent females (ages 15-18 years) with overweight or obesity completed a social stress induction task in which they were told they would be rated by peers based on their photograph and profile. Participants were randomly assigned to one night of sleep deprivation or 9 h of sleep the night before undergoing fMRI while receiving positive and negative evaluations from their peers. After which, subjects participated in an ad libitum buffet. RESULTS: Sleep deprived, relative to nondeprived girls had distinct patterns of neural engagement to positive and negative evaluation in anterior, mid, and posterior aspects of midline brain structures. Moreover, a sleep deprivation-by-evaluation valence-by-caloric intake interaction emerged in bilateral dorsal anterior cingulate. Among sleep deprived girls, greater engagement during negative, but not positive, feedback was associated with lower caloric intake. This was not observed for nonsleep deprived girls. CONCLUSIONS: Results suggest an interaction between acute sleep loss and social evaluation that predicts emotion-related neural activation and caloric intake in adolescents. This research helps to elucidate the relationship between sleep loss, social stress, and weight status using a novel health neuroscience model.

Development and Psychometric Evaluation of the PROMIS Pediatric Pain Intensity Measure in Children and Adolescents with Chronic Pain.

The goal of the current study was to enhance the measurement of the pediatric chronic pain experience through a methodologically rigorous approach. This paper outlines the development and initial validation of a pain intensity measure for pediatric patients with chronic pain using Patient-Reported Outcomes Measurement Information System methodology. Measure development incorporated feedback from children with painful conditions. Based on input from pediatric participants and content experts, 4 candidate items assessing pain intensity were included for large scale testing. Children completed self-report items pertaining to their pain experience that were developed as part of a larger pool of new candidate Patient-Reported Outcomes Measurement Information System pediatric pain domain items as well as measures of pain interference, depressive symptoms, fatigue, pain behavior, pain intensity, and pain catastrophizing. The final sample for the large scale testing included N = 442 pediatric patients between the ages 8 to 18 years (Mean age = 13.54, Standard Deviation = 2.78; 71.27% female) experiencing chronic pain. Psychometric analysis resulted in a final measure that included 3 items with evidence of reliability (Cronbach alpha = .82) and convergent validity. The Likert format of the response options may be preferable to the traditional numeric rating scale for use in pediatric populations who experience chronic pain based on patients' feedback, which was directly utilized in designing the scale. Further, the inclusion of fewer and clinically meaningful response options should reduce ambiguity for young respondents. PERSPECTIVE: We have developed and evaluated a clinically sensitive and psychometrically precise 3-item pain intensity measure with Likert-type responses for self-report use among children and adolescents ages 8 to 18 years with chronic pain. Development of the item content and response options included input from children and adolescents with chronic pain. The development of pain intensity items with pediatric appropriate language, and labeled, fewer response options to yield maximal clinically meaningful information improves the precision of pain intensity measurement in children.

White matter integrity disparities between normal-weight and overweight/obese adolescents: an automated fiber quantification tractography study.

Obese adults have been shown to have poorer white brain matter integrity relative to normal-weight peers, but few studies have tested whether white matter integrity is compromised in overweight and obese adolescents. Also, it is unclear if age interacts with body mass to affect white matter integrity in adolescents. We used Automated Fiber Quantification, a tractography method, to compare fractional anisotropy between normal-weight and overweight/obese adolescents in the corpus callosum, corticospinal tract, cingulum, inferior fronto-occipital fasciculus, and uncinate fasciculus. Further, we tested whether any differences were moderated by age. Forty-seven normal-weight and forty overweight/obese adolescents were scanned using a diffusion tensor imaging (DTI) scan sequence. Overweight/obese compared to normal-weight adolescents had decreased white matter integrity in the superior frontal corpus callosum, left and right uncinate fasciculi, left inferior fronto-occipital fasciculus, and left corticospinal tract, which may be related to heightened reward processing. Overweight/obese compared to normal-weight adolescents had increased white matter integrity in the orbital and anterior frontal corpus callosum, right inferior fronto-occipital fasciculus, left cingulum, and left corticospinal tract, which may be related to heightened attentional processing. As age increased, six tracts showed poorer white matter integrity as body mass index percentile (BMI%) increased, but three tracts showed greater white matter integrity as BMI% increased. Future research examining associations between white matter integrity and neural indices of food-related reward and attention are needed to clarify the functional significance of white matter integrity discrepancies between normal-weight and overweight/obese adolescents.

Sleep duration differentially affects brain activation in response to food images in adolescents with overweight/obesity compared to adolescents with normal weight.

STUDY OBJECTIVES: Sleep is an important behavior that affects appetite and eating in adolescents. Our study examined food-related neural activation in brain regions associated with food reward and inhibition in adolescents under sleep-restricted and well-rested conditions. METHODS: In this within-subjects study, 52 adolescents (ages 12-18; 46% female; M age = 15.96 years, SD = 1.56) with normal weight (NW; N = 29, M body mass index % [BMI%] = 54.55, SD = 24.54) or overweight/obesity (OV/OB; N = 23, M BMI% = 93.78, SD = 4.60) spent 5 hours in bed at home each night for five consecutive nights and 9 hours in bed at home each night for 5 consecutive nights, with the first day of each condition occurring 4 weeks apart. The morning following each sleep modification period, functional magnetic resonance imaging (fMRI) data were collected while participants performed an inhibitory (go/no-go) task with food stimuli. RESULTS: We found significantly greater activation in brain regions associated with inhibition in adolescents with NW in response to food cues when sleep restricted. No increase in inhibition-related neural activation was observed in adolescents with OV/OB when sleep restricted. We also found neural activation consistent with greater reward processing associated with food cues following sleep restriction regardless of weight status. CONCLUSIONS: These findings suggest that chronic sleep restriction may increase the likelihood of suboptimal dietary behavior for adolescents with OV/OB because they do not experience increased inhibition-related neural responding to counter possible increased reward-related neural responding following sleep restriction.

Establishing clinical meaning and defining important differences for Patient-Reported Outcomes Measurement Information System (PROMIS®) measures in juvenile idiopathic arthritis using standard setting with patients, parents, and providers.

BACKGROUND: Patient-Reported Outcomes Measurement Information System (PROMIS) measures are used increasingly in clinical care. However, for juvenile idiopathic arthritis (JIA), scores lack a framework for interpretation of clinical severity, and minimally important differences (MID) have not been established, which are necessary to evaluate the importance of change. METHODS: We identified clinical severity thresholds for pediatric PROMIS measures of mobility, upper extremity function (UE), fatigue, and pain interference working with adolescents with JIA, parents of JIA patients, and clinicians, using a standard setting methodology modified from educational testing. Item parameters were used to develop clinical vignettes across a range of symptom severity. Vignettes were ordered by severity, and panelists identified adjacent vignettes considered to represent upper and lower boundaries separating category cut-points (i.e., from none/mild problems to moderate/severe). To define MIDs, panelists reviewed a full score report for the vignettes and indicated which items would need to change and by how much to represent "just enough improvement to make a difference." RESULTS: For fatigue and UE, cut-points among panels were within 0.5 SD of each other. For mobility and pain interference, cut-scores among panels were more divergent, with parents setting the lowest cut-scores for increasing severity. The size of MIDs varied by stakeholders (parents estimated largest, followed by patients, then clinicians). MIDs also varied by severity classification of the symptom. CONCLUSIONS: We estimated clinically relevant severity cut-points and MIDs for PROMIS measures for JIA from the perspectives of multiple stakeholders and found notable differences in perspectives.

Pressure Pain Threshold and Anxiety in Adolescent Females With and Without Juvenile Fibromyalgia: A Pilot Study.

OBJECTIVES: Reduced pain thresholds have been documented in adult fibromyalgia, but there are no quantitative studies of altered pain sensitivity in adolescents with juvenile fibromyalgia (JFM). The current study examined differences in pressure pain sensitivity between adolescent females with JFM and healthy controls. The relationship between levels of anxiety and pain were also examined. METHODS: A total of 34 JFM (15.4±1.4 y old) and 31 controls (14.5±1.3 y old) completed self-report measures of pain and anxiety. Pressure pain threshold was assessed (palm and forehead sites) with a hand-held algometer. Participants indicated the first sensation of pain and then rated the intensity of pain on a Numerical Rating Scale. RESULTS: Adolescents with JFM exhibited greater sensitivity to pressure pain compared with controls. While the difference between JFM and controls was only observed at the forehead, the intensity of pain produced by the pressure algometry at both sites was significantly higher in the JFM participants compared with controls. Correlations between clinical pain and anxiety were significant for the JFM group only. No relationships were observed between anxiety and pressure pain for either group. DISCUSSION: This study is a first step toward investigating mechanisms of altered pain processing in adolescents with JFM. Adolescents with JFM were found be more sensitive to pressure pain than their healthy peers, which suggests a propensity for sensitization of peripheral and/or central nociceptive information often reported in adult fibromyalgia, and which does not appear to be affected by anxiety.

Motivational Impact of Palatable Food Correlates With Functional Brain Responses to Food Images in Adolescents.

Objective: To examine associations between motivational impact of palatable foods and neural activity in brain regions involved in inhibitory control among adolescents. Methods: Thirty-four adolescents aged 14-20 years underwent functional magnetic resonance imaging while viewing images of high- and low-energy foods. Participants completed the Power of Food Scale (PFS). Whole-brain analyses of variance tested for neural activation differences and correlations between brain activation and PFS scores were tested. Results: We found an interaction between food type (high energy vs. low energy) and PFS scores in the right dorsolateral prefrontal cortex and right inferior parietal lobule. We also found that PFS scores correlated negatively with activation to high-energy foods in prefrontal cortical and parietal regions. Conclusions: These findings suggest that individuals with high motivation for high-energy foods also demonstrate lower neural activation in inhibition-related brain regions when viewing images of high-energy foods, indicating that they may have difficulty inhibiting consumption impulses.

Appropriateness of the food-pics image database for experimental eating and appetite research with adolescents.

BACKGROUND: Research examining effects of visual food cues on appetite-related brain processes and eating behavior has proliferated. Recently investigators have developed food image databases for use across experimental studies examining appetite and eating behavior. The food-pics image database represents a standardized, freely available image library originally validated in a large sample primarily comprised of adults. The suitability of the images for use with adolescents has not been investigated. The aim of the present study was to evaluate the appropriateness of the food-pics image library for appetite and eating research with adolescents. METHODS: Three hundred and seven adolescents (ages 12-17) provided ratings of recognizability, palatability, and desire to eat, for images from the food-pics database. Moreover, participants rated the caloric content (high vs. low) and healthiness (healthy vs. unhealthy) of each image. RESULTS: Adolescents rated approximately 75% of the food images as recognizable. Approximately 65% of recognizable images were correctly categorized as high vs. low calorie and 63% were correctly classified as healthy vs. unhealthy in 80% or more of image ratings. These results suggest that a smaller subset of the food-pics image database is appropriate for use with adolescents. CONCLUSIONS: With some modifications to included images, the food-pics image database appears to be appropriate for use in experimental appetite and eating-related research conducted with adolescents.

Neonates and Infants Discharged Home Dependent on Medical Technology: Characteristics and Outcomes.

BACKGROUND: Preterm neonates and neonates with complex conditions admitted to a neonatal intensive care unit (NICU) may require medical technology (eg, supplemental oxygen, feeding tubes) for their continued survival at hospital discharge. Medical technology introduces another layer of complexity for parents, including specialized education about neonatal assessment and operation of technology. The transition home presents a challenge for parents and has been linked with greater healthcare utilization. PURPOSE: To determine incidence, characteristics, and healthcare utilization outcomes (emergency room visits, rehospitalizations) of technology-dependent neonates and infants following initial discharge from the hospital. METHODS: This descriptive, correlational study used retrospective medical record review to examine technology-dependent neonates (N = 71) upon discharge home. Study variables included demographic characteristics, hospital length of stay, and type of medical technology used. Analysis of neonates (n = 22) with 1-year postdischarge data was conducted to identify relationships with healthcare utilization. Descriptive and regression analyses were performed. FINDINGS: Approximately 40% of the technology-dependent neonates were between 23 and 26 weeks' gestation, with birth weight of less than 1000 g. Technologies used most frequently were supplemental oxygen (66%) and feeding tubes (46.5%). The mean total hospital length of stay for technology-dependent versus nontechnology-dependent neonates was 108.6 and 25.7 days, respectively. Technology-dependent neonates who were female, with a gastrostomy tube, or with longer initial hospital length of stay were at greater risk for rehospitalization. IMPLICATIONS FOR PRACTICE: Assessment and support of families, particularly mothers of technology-dependent neonates following initial hospital discharge, are vital. IMPLICATIONS FOR RESEARCH: Longitudinal studies to determine factors affecting long-term outcomes of technology-dependent infants are needed.

Longitudinal evaluation of patient-reported outcomes measurement information systems measures in pediatric chronic pain.

The Patient-Reported Outcomes Measurement Information System (PROMIS) initiative is a comprehensive strategy by the National Institutes of Health to support the development and validation of precise instruments to assess self-reported health domains across healthy and disease-specific populations. Much progress has been made in instrument development, but there remains a gap in the validation of PROMIS measures for pediatric chronic pain. The purpose of this study was to investigate the construct validity and responsiveness to change of 7 PROMIS domains for the assessment of children (ages: 8-18) with chronic pain--Pain Interference, Fatigue, Anxiety, Depression, Mobility, Upper Extremity Function, and Peer Relationships. The PROMIS measures were administered at the initial visit and 2 follow-up visits at an outpatient chronic pain clinic (CPC; N = 82) and at an intensive amplified musculoskeletal pain day-treatment program (N = 63). Aim 1 examined construct validity of PROMIS measures by comparing them with corresponding "legacy" measures administered as part of usual care in the CPC sample. Aim 2 examined sensitivity to change in both CPC and amplified musculoskeletal pain samples. Longitudinal growth models showed that PROMIS' Pain Interference, Anxiety, Depression, Mobility, Upper Extremity, and Peer Relationship measures and legacy instruments generally performed similarly with slightly steeper slopes of improvement in legacy measures. All 7 PROMIS domains showed responsiveness to change. Results offered initial support for the validity of PROMIS measures in pediatric chronic pain. Further validation with larger and more diverse pediatric pain samples and additional legacy measures would broaden the scope of use of PROMIS in clinical research.

A Qualitative Examination of a New Combined Cognitive-Behavioral and Neuromuscular Training Intervention for Juvenile Fibromyalgia.

OBJECTIVES: Adolescents with juvenile fibromyalgia (JFM) are typically sedentary despite recommendations for physical exercise, a key component of pain management. Interventions such as cognitive-behavior therapy (CBT) are beneficial but do not improve exercise participation. The objective of this study was to obtain preliminary information about the feasibility, safety, and acceptability of a new intervention--Fibromyalgia Integrative Training for Teens (FIT Teens), which combines CBT with specialized neuromuscular exercise training modified from evidence-based injury prevention protocols. MATERIALS AND METHODS: Participants were 17 adolescent females (aged 12 to 18 y) with JFM. Of these, 11 completed the 8-week (16 sessions) FIT Teens program in a small-group format with 3 to 4 patients per group. Patients provided detailed qualitative feedback via individual semistructured interviews after treatment. Interview content was coded using thematic analysis. Interventionist feedback about treatment implementation was also obtained. RESULTS: The intervention was found to be feasible, well tolerated, and safe for JFM patients. Barriers to enrollment (50% of those approached) included difficulties with transportation or time conflicts. Treatment completers enjoyed the group format and reported increased self-efficacy, strength, and motivation to exercise. Participants also reported decreased pain and increased energy levels. Feedback from participants and interventionists was incorporated into a final treatment manual to be used in a future trial. DISCUSSION: Results of this study provided initial support for the new FIT Teens program. An integrative strategy of combining pain coping skills via CBT enhanced with tailored exercise specifically designed to improve confidence in movement and improving activity participation holds promise in the management of JFM.

2010 American College of Rheumatology Adult Fibromyalgia Criteria for Use in an Adolescent Female Population with Juvenile Fibromyalgia.

OBJECTIVES: To evaluate the utility of the 2010 American College of Rheumatology (ACR) adult fibromyalgia criteria for use in adolescents with juvenile fibromyalgia (JFM). STUDY DESIGN: Participants included 47 adolescent girls diagnosed with JFM (mean age = 15.3 years) and 48 age- and sex-matched adolescents (mean age = 15.0 years) with localized chronic pain (eg, headaches or abdominal pain). A trained examiner administered the Widespread Pain Index and Symptom Severity measures and also completed a manual tender point exam. Clinicians completed a form indicating the presence of active JFM per Yunus and Masi (1985) criteria, the only available and most commonly used measure for JFM. Criterion validity analysis was performed as well as t tests comparing symptoms between JFM and controls. RESULTS: With the Yunus and Masi criteria used as the gold standard, the 2010 ACR fibromyalgia criteria showed a sensitivity of 89.4% and specificity of 87.5%. CONCLUSION: The 2010 ACR measure appears to be a valuable tool for the identification of JFM. However, a slight modification to the 2010 ACR measure and inclusion of a clinical exam is recommended.

Qualitative Evaluation of Pediatric Pain Behavior, Quality, and Intensity Item Candidates and the PROMIS Pain Domain Framework in Children With Chronic Pain.

UNLABELLED: As initial steps in a broader effort to develop and test pediatric pain behavior and pain quality item banks for the Patient-Reported Outcomes Measurement Information System (PROMIS), we used qualitative interview and item review methods to 1) evaluate the overall conceptual scope and content validity of the PROMIS pain domain framework among children with chronic/recurrent pain conditions, and 2) develop item candidates for further psychometric testing. To elicit the experiential and conceptual scope of pain outcomes across a variety of pediatric recurrent/chronic pain conditions, we conducted 32 semi-structured individual and 2 focus-group interviews with children and adolescents (8-17 years), and 32 individual and 2 focus-group interviews with parents of children with pain. Interviews with pain experts (10) explored the operational limits of pain measurement in children. For item bank development, we identified existing items from measures in the literature, grouped them by concept, removed redundancies, and modified the remaining items to match PROMIS formatting. New items were written as needed and cognitive debriefing was completed with the children and their parents, resulting in 98 pain behavior (47 self, 51 proxy), 54 quality, and 4 intensity items for further testing. Qualitative content analyses suggest that reportable pain outcomes that matter to children with pain are captured within and consistent with the pain domain framework in PROMIS. PERSPECTIVE: PROMIS pediatric pain behavior, quality, and intensity items were developed based on a theoretical framework of pain that was evaluated by multiple stakeholders in the measurement of pediatric pain, including researchers, clinicians, and children with pain and their parents, and the appropriateness of the framework was verified.

Child pain catastrophizing mediates the relation between parent responses to pain and disability in youth with functional abdominal pain.

OBJECTIVES: Functional abdominal pain (FAP) in youth is associated with substantial impairment in functioning, and prior research has shown that overprotective parent responses can heighten impairment. Little is known about how a range of parental behaviors (overprotection, minimizing, and/or encouragement) in response to their child's pain interact with child coping characteristics (eg, catastrophizing) to influence functioning in youth with FAP. In this study, it was hypothesized that the relation between parenting factors and child disability would be mediated by children's levels of maladaptive coping (ie, pain catastrophizing). METHODS: Seventy-five patients with FAP presenting to a pediatric pain clinic and their caregivers participated in the study. Youth completed measures of pain intensity (Numeric Rating Scale), pain catastrophizing (Pain Catastrophizing Scale), and disability (Functional Disability Inventory). Caregivers completed measures of parent pain catastrophizing (Pain Catastrophizing Scale), and parent responses to child pain behaviors (Adult Responses to Child Symptoms: Protection, Minimizing, and Encouragement/Monitoring subscales). RESULTS: Increased functional disability was significantly related to higher child pain intensity, increased child and parent pain catastrophizing, and higher levels of encouragement/monitoring and protection. Parent minimization was not related to disability. Child pain catastrophizing fully mediated the relation between parent encouragement/monitoring and disability and partially mediated the relation between parent protectiveness and disability. CONCLUSIONS: The impact of parenting behaviors in response to FAP on child disability is determined, in part, by the child's coping style. Findings highlight a more nuanced understanding of the parent-child interaction in determining pain-related disability levels, which should be taken into consideration in assessing and treating youth with FAP.

Quality of life and emotional functioning in youth with chronic migraine and juvenile fibromyalgia.

SUMMARY: Chronic pain in children is associated with significant negative impact on social, emotional, and school functioning. Previous studies on the impact of pain on children's functioning have primarily used mixed samples of pain conditions or single pain conditions (eg, headache and abdominal pain) with relatively small sample sizes. As a result, the similarities and differences in the impact of pain in subgroups of children with chronic pain have not been closely examined. OBJECTIVE: To compare pain characteristics, quality of life, and emotional functioning among youth with pediatric chronic migraine (CM) and juvenile fibromyalgia (JFM). METHODS: We combined data obtained during screening of patients for 2 relatively large intervention studies of youth (age range, 10 to 18 y) with CM (N=153) and JFM (N=151). Measures of pain intensity, quality of life (Pediatric Quality of Life; PedsQL, child and parent-proxy), depressive symptoms (Children's Depression Inventory), and anxiety symptoms (Adolescent Symptom Inventory-4-Anxiety subscale) were completed by youth and their parent. A multivariate analysis of covariance controlling for effects of age and sex was performed to examine differences in quality of life and emotional functioning between the CM and JFM groups. RESULTS: Youth with JFM had significantly higher anxiety and depressive symptoms, and lower quality of life in all domains. Among children with CM, overall functioning was higher but school functioning was a specific area of concern. DISCUSSION: Results indicate important differences in subgroups of pediatric pain patients and point to the need for more intensive multidisciplinary intervention for JFM patients.

Qualitative analysis of parent experiences with achieving cystic fibrosis nutrition recommendations.

BACKGROUND: A combined behavior-nutrition approach is recommended for children with CF with growth deficits. The present study aimed to use a qualitative approach to 1) understand families' experiences using behavior-nutrition intervention strategies and 2) identify the challenges with CF management families experienced during the developmental transition between toddlerhood and early school-age. METHODS: Eight families (mean age of children=8.2 years) participated in a semistructured interview. Themes were independently identified by three coders, confirmed via consensus, and compared to a reliability coder. RESULTS: Parents discussed behavior and nutrition strategies, ongoing challenges with nutrition and behavior, new challenges, and protective factors. Challenges included transition to school, transfer of treatment responsibility, picky eating, and parental stress. CONCLUSIONS: Ongoing assessment and recommendations to address parent stress and child behavior are warranted. Providing families with anticipatory guidance can better prepare families for challenging developmental transitions including starting school and the transfer of treatment responsibility.

The aryl hydrocarbon receptor is required for normal gonadotropin responsiveness in the mouse ovary.

The aryl hydrocarbon receptor (AHR) mediates the toxicity of a variety of environmental chemicals. Although little is known about the physiological role of the AHR, studies suggest that it plays an important role in regulating ovulation because Ahr deficient (AhRKO) mice have a reduced number of ovulations compared to wild-type (WT) mice. The reasons for the reduced ability of AhRKO mice to ovulate are unknown. Normal ovulation, however, requires estrous cyclicity, appropriate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and LH and FSH responsiveness. Thus, the purpose of this study was to test the hypothesis that Ahr deletion regulates ovulation by altering cyclicity, FSH and LH levels, follicle-stimulating hormone receptor (Fshr) and luteinizing hormone receptor (Lhcgr) levels and/or gonadotropin responsiveness. The data indicate that AhRKO and WT mice have similar levels of FSH and LH, but AhRKO mice have reduced Fshr and Lhcgr mRNA levels compared to WT mice. Furthermore, AhRKO ovaries contain fewer corpora lutea compared to WT ovaries after 5 IU equine chorionic gonadotropin (eCG) treatment. Lastly, both AhRKO and WT mice ovulate a similar number of eggs in response to 5 IU human chorionic gonadotropin (hCG), but AhRKO mice ovulate fewer eggs than WT mice in response to 2.5 IU and 1.25 IU hCG. Collectively, these data indicate that AhRKO follicles have a reduced capacity to ovulate compared to WT follicles and that this is due to reduced responsiveness to gonadotropins. Thus, in addition to mediating toxicity of environmental chemicals, the Ahr is required for normal ovulation.

The aryl hydrocarbon receptor affects mouse ovarian follicle growth via mechanisms involving estradiol regulation and responsiveness.

The aryl hydrocarbon receptor (AHR) is a known transcription factor. Although studies indicate that Ahr-deficient (AhRKO) mice have defects in female reproduction, only a few studies have examined the role of AHR in the ovary. Previous studies have suggested, without directly testing, that AhRKO mice have slower follicular growth than wild-type (WT) mice. Therefore, the first objective of the present study was to examine whether AhRKO follicles grow slower than WT follicles and if so, to determine whether the mechanism by which Ahr affects follicular growth is through effects on antrum size, granulosa cell proliferation, and regulators of cell cycle progression. Since estradiol (E(2)) is critical for the normal growth of ovarian follicles, the second objective of the present study was to determine the role of Ahr in regulating E(2) production and responsiveness. The third objective of the present study was to determine whether E(2) replacement restores follicular growth of AhRKO follicles to WT levels in vitro. We found that AhRKO follicles grew slower than WT follicles in vitro. While AhRKO and WT follicles had similar antrum sizes, AhRKO follicles showed decreased granulosa cell proliferation and reduced mRNA and protein levels of cell cycle regulators, as compared to WT follicles. Furthermore, the AhRKO mice had lower serum and follicle-produced E(2) levels and showed decreased Esr1 and Esr2 mRNA levels compared to WT mice. Finally, E(2) treatment of AhRKO follicles restored follicular growth to WT levels in vitro. Collectively, these findings suggest that the AHR affects follicular growth via mechanisms that involve E(2) regulation and responsiveness.