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. 2020 Aug 18;23(2):231–237. doi: 10.1177/1099800420948589

Sex Hormones, BDNF, Leptin, and TGF-β1 in Females With IBS: A Pilot Investigation

Kristen R Weaver 1,2,✉, Christina M Boulineaux 3, Jeffrey M Robinson 4, Kierra Butler 2, Margaret M Heitkemper 5, Wendy A Henderson 6
PMCID: PMC8264858  PMID: 32806924

Abstract

Background:

Irritable bowel syndrome (IBS) is a chronic gastrointestinal condition predominantly affecting the female sex, and is characterized by brain-gut axis dysregulation. Relevance of hormones along the hypothalamic-pituitary gonadal axis and hypothalamic-pituitary adrenal axis to IBS symptomatology remain unclear, as does the significance of other modulators including brain derived neurotrophic factor (BDNF), leptin, and transforming growth factor βeta 1 (TGF-β1).

Methods:

Females with IBS were compared with female healthy controls (HC) on age, race, hormonal contraceptive use, body mass index, adrenocorticotropic hormone, cortisol, estradiol, follicular stimulating hormone, luteinizing hormone, progesterone, total cholesterol, Center for Epidemiological Studies Depression Scale (CES-D) and Perceived Stress Scale (PSS). BDNF, leptin, and TGF-β1 were quantified using enzyme-linked immunosorbent assay. Descriptive statistics, non-parametric techniques, and regression analyses were performed.

Results:

Participants with IBS (n = 12) displayed higher estradiol (p = .027) than did HC (n = 21). Direction of associations among study variables often differed between groups: BDNF and progesterone in HC (rs = .623) and in IBS (rs = −.723). The relationship between log (CES-D) and log (estradiol) varied by IBS status (interaction term p = 0.019).

Discussion:

Elevated estradiol in participants with IBS, and differential patterns of biological and psychological indices between groups, encourages further inquiry on the relevance of sex hormones, BDNF, leptin, and TGF-β1 to symptoms of IBS. Future research endeavors should conduct longitudinal quantification of sex hormones with subjective symptom assessment to facilitate insight on the pathophysiology and female sex bias in IBS.

Keywords: irritable bowel syndrome, IBS, sex hormones, BDNF, leptin, TGF-β1

Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) condition characterized by abdominal pain and alterations in bowel habits (Lacy et al., 2016), that predominantly affects the female sex (Sperber et al., 2017) and is frequently comorbid with psychological disorders, such as anxiety and depression (Ballou et al., 2015). Symptoms of IBS often fluctuate across the menstrual cycle, and although sex hormones are known to have modulatory effects upon GI motility, permeability, and pain (Meleine & Matricon, 2014), their role in symptom manifestation of IBS is not fully understood. Relationships among hormones along the hypothalamic-pituitary gonadal (HPG) axis and hypothalamic-pituitary adrenal (HPA) axis are not adequately characterized in patients with IBS, nor has their relevance to other modulators along the brain-gut axis (BGA) been established. The disorder of IBS imposes significant financial burden and adversely affects individuals’ work productivity, activities of daily living, and health-related quality of life (Chang et al., 2018). Therefore, enhanced understanding of the brain-gut connection in IBS is urgently needed and further inquiry is warranted as to the role of sex hormones and other modulators of the BGA in patient symptomatology.

Sex hormones can exert regulatory effects upon the HPA axis, as demonstrated extensively in animal studies (Roca et al., 2003) and in human subjects. For instance, healthy female subjects display differential activation of stress response circuitry, as noted through functional magnetic resonance imaging, dependent upon menstrual cycle phase (early follicular versus mid cycle; Goldstein et al., 2010). Stress is relevant to the disorder of IBS, with patients reporting significantly higher levels of perceived stress than healthy controls (HC; Weaver et al., 2018a), and patients with IBS noted to display a dysregulated stress response. This includes both a sustained HPA axis response (Kennedy et al., 2014), and a blunted HPA axis response (Suarez-Hitz et al., 2012) as measured via salivary cortisol during the Trier Social Stress Test. Stress also impacts severity of abdominal pain and bowel symptoms in patients with IBS (Blanchard et al., 2008). Therefore, a greater understanding of how sex hormones influence stress and symptomatology in IBS is required. Given that a mediator of stress may rely upon actions of other mediators (McEwen et al., 2015), three proteins with documented relevance to IBS were evaluated alongside sex hormones for significance in this investigation: brain derived neurotrophic factor (BDNF), leptin, and transforming growth factor βeta 1 (TGF-β1).

BDNF, a neurotrophin with roles in neuronal differentiation, outgrowth, and repair (Monteleone & Maj, 2013), contributes to estrogen’s actions in the brain and, in turn, is upregulated in response to estrogen (Scharfman & MacLusky, 2014). Low levels of serum BDNF have been reported in depressed individuals (Karege et al., 2002), whereas increased levels of BDNF have been reported in colonic biopsies of patients with IBS compared with HC, with levels positively associated with severity and frequency of abdominal pain (Yu et al., 2012). Leptin, a hormone secreted largely by adipocytes, is involved in energy homeostasis, appetite regulation (Xing et al., 2015), and the stress response (Haleem, 2014), and can exert direct effects along the HPG axis (Licinio et al., 1998). Significantly lower levels of leptin and higher levels of perceived stress have been reported in patients with IBS in comparison to HC (Semnani et al., 2009). Lastly, TGF-β1, a multifunctional and pleiotropic cytokine, is involved with processes surrounding cellular differentiation, proliferation, inflammation, and fibrosis (Yang et al., 2014), and has been reported as diminished in the peripheral blood of patients with IBS compared with HC (Weaver et al., 2018b). Expression levels of TGF-β have also been reported as reduced in the colonic biopsies of patients with IBS compared with HC (Macsharry et al., 2008), and importantly, TGFβ exhibits bidirectional signaling with estrogen receptor α, as extensively studied in the field of breast cancer research (Siersbaek et al., 2018). Preclinical and clinical studies demonstrate the relevance of sex hormones, BDNF, leptin, and TGF-β1 to GI symptoms, stress and mood, and prompt the current exploratory investigation in females with IBS. The purpose of this pilot study is to evaluate participants with IBS compared with HC, examine patterns of associations among biological and psychological indices, and further our understanding of the brain-gut connection in the disorder of IBS.

Materials and Methods

This study was conducted under a parent investigation at the National Institutes of Health (NIH) in Bethesda, MD entitled “Brain-Gut Interactions in Overweight and Normal Weight Patients With Chronic Abdominal Pain” (NCT00824941). The purpose of the parent investigation was to evaluate the role of inflammation in normal weight and overweight participants, both with and without chronic abdominal pain. Males and females were recruited, 13–45 years of age, with females required to have onset of menses at least 2 years prior to study participation. For participants with abdominal pain, symptoms were required to be present for at least 6 months. Any participant with gastrointestinal, cardiac, pulmonary, endocrine, neurologic, renal, or gynecological pathology was excluded. In addition, any participant with a severe psychiatric condition or severe comorbid pain condition was excluded. Protocol exclusions also addressed certain types of daily medications (acting on the cortisol, serotonergic, or catecholaminergic systems), consumption of > 300 mg caffeine in afternoon-evening, >2 servings of alcohol daily, or engagement in late evening or night work. Participants who met inclusion criteria during initial telephone screening were scheduled for a fasting morning appointment, with females scheduled between days 3 and 10 following onset of menses. During the study visit, informed, written consent was obtained, questionnaires were completed, and peripheral blood specimens were drawn. A history and physical examination was performed by a health care provider (nurse practitioner or medical doctor) and IBS diagnosis and subtype were identified per Rome III Criteria (Longstreth et al., 2006).

Measures

Demographic characteristics were collected in the parent investigation using the socio-demographic questionnaire developed by the Center for Research in Chronic Disorders, University of Pittsburgh School of Nursing (1999). For this study, self-reported information on age, sex, and race were incorporated for analyses. In addition, information regarding hormonal contraceptive use and BMI were included. Assessment of participant height and weight was performed in duplicate per the parent protocol, with BMI calculated by the following formula: BMI = kg/m2. Participant responses to the Perceived Stress Scale (PSS; Cohen et al., 1983) and Center for Epidemiological Studies Depression Scale (CES-D; Radloff, 1977) were reviewed to assess symptoms of life stress and depression, respectively.

Laboratory Assays

Follicular stimulating hormone (FSH), luteinizing hormone (LH), cortisol, adrenocorticotropic hormone (ACTH), and total cholesterol were collected per protocol of the parent study, and processed by the NIH Department of Laboratory Medicine (DLM). To quantify levels of estradiol and progesterone, previously collected and frozen serum samples (−80 °C) from the same peripheral blood draw, were measured at the DLM via electrochemiluminescence technology (Roche cobas 6000 analyzer). Lower limits of detection were 5.0 pg/mL and 0.03 ng/mL, respectively. To quantify peripheral levels of BDNF, leptin, and TGF-β1, enzyme-linked immunosorbent assays were performed upon previously collected and frozen serum samples (−80 °C) per manufacturer’s instructions (Human Quantikine ELISA kits, R&D Systems). Reported sensitivity of the BDNF, leptin, and TGF-β1 assays were 20 pg/mL, 7.8 pg/mL, and 4.61 pg/mL respectively, and samples were run in triplicate.

Data Analyses

To evaluate demographic and clinical variables of interest and relationships among variables between groups, descriptive statistics, nonparametric techniques, and regression analyses were performed on SPSS Version 26 (Released 2019. IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp.) with level of significance set a priori as p < .05. To obtain effect size estimates for Mann-Whitney U results, z values were used to calculate r = z/√N; Fritz et al., 2012) as proposed by Cohen (1977). Given that biological factors such as age and BMI may influence the measurement of steroid hormones (Stanczyk & Clarke, 2010), participants were categorized into groupings for these two factors when performing regression analyses. Age was categorized as less than 30 years old, and as 30 years old and greater, and BMI was categorized as less than 25 (normal weight), and as 25 and greater (overweight). As gonadal steroids are derived from cholesterol (Barbieri, 2014), levels of cholesterol were controlled for during regression analyses. Lastly, variables of interest were log-transformed to address assumptions of normal distribution.

Results

Demographic and Clinical Characteristics

Data were analyzed for 47 females (average age 28.1 years), of whom 18 were participants with IBS and 29 served as HC. Four samples were excluded from further analyses due to hormone levels (progesterone and LH) markedly above the 95% percentile, as these subjects were likely not evaluated during days 3–10 of their menstrual cycle. Of the remaining 43 participants, 10 endorsed hormonal contraceptive use whereas 33 did not; these two groups did not differ in terms of IBS diagnosis (Fisher’s Exact Test, p = .275), nor age (Mann Whitney U, p = .105). Given the study’s aim to explore endogenous sex hormones in IBS, participants who used hormonal contraceptives were excluded from further analyses, yielding a final sample of 33 participants as shown in Table 1 (average age 29 years; 12 with IBS, 21 as HC). Of the 12 included participants with IBS, two reported predominant bowel symptoms of IBS-diarrhea (17%), eight with IBS-constipation (67%), one with IBS-mixed (8%), and one with IBS-unspecified (8%).

Table 1.

Demographic and Clinical Characteristics of Study Participants.

Variable Total (N = 33) HC (n = 21) IBS (n = 12) p r
Race, n (%)
Asian 3 (9) 2 (10) 1 (8)
African American 15 (46) 9 (43) 6 (50)
Caucasian 11 (33) 8 (38) 3 (25)
Mixed/other 4 (12) 2 (10) 2 (17)
Age Category 1.00
< 30 years 17 11 6
≥ 30 years 16 10 6
Weight Category .469
BMI < 25 15 11 4
BMI ≥ 25 18 10 8
Variable (M, SD)
ACTH (pg/mL) M = 17.3, SD = 9.85 M = 17.0, SD = 10.35 M = 17.8, SD = 9.31 .542 .108
Age (years) M = 29.0, SD = 7.05 M = 29.2, SD = 8.15 M = 28.5, SD = 4.82 .956 .01
BDNF (ng/mL)* M = 7.8, SD = 7.83 M = 8.8, SD = 9.09 M = 5.9, SD = 4.78 .559 .125
BMI (kg/m2) M = 28.1, SD = 6.83 M = 27.9, SD = 7.36 M = 28.4, SD = 6.10 .618 .088
CES-D M = 9.4, SD = 7.16 M = 8.6, SD = 7.52 M = 10.8, SD = 6.53 .131 .268
Cholesterol (mg/dL)† M = 169.0, SD = 28.63 M = 169.7, SD = 30.41 M = 167.9, SD = 26.66 .924 .017
Cortisol (mcg/dL) M = 9.1, SD = 3.45 M = 9.7, SD = 3.33 M = 8.1, SD = 3.59 .242 .209
Estradiol (pg/mL) M = 73.5, SD = 49.18 M = 61.7, SD = 45.34 M = 94.1, SD = 50.66 .027 .384
FSH (U/L) M = 7.1, SD = 5.57 M = 7.6, SD = 6.80 M = 6.1, SD = 2.13 .985 .006
Leptin (ng/mL) M = 26.1, SD = 21.08 M = 26.0, SD = 23.42 M = 26.4, SD = 17.17 .449 .137
LH (U/L) M = 4.5, SD = 2.61 M = 4.8, SD = 3.05 M = 3.9, SD = 1.53 .567 .101
Progesterone (ng/mL) M = 1.4, SD = 2.59 M = 1.0, SD = 1.85 M = 2.2, SD = 3.52 .258 .201
PSS M = 12.8, SD = 6.80 M = 11.1, SD = 6.97 M = 15.8, SD = 5.52 .063 .326
TGF-β1 (ng/mL) M = 5.1, SD = 5.14 M = 5.4, SD = 5.75 M = 4.6, SD = 4.06 .645 .085
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Note. Sample size *n = 25, †n = 32. ACTH = adrenocorticotropic hormone, BDNF = brain-derived neurotrophic factor, BMI = body mass index, CES-D = Center for Epidemiological Studies Depression Scale, FSH = follicular stimulating hormone, HC = healthy controls, IBS = irritable bowel syndrome, LH = luteinizing hormone, PSS = Perceived Stress Scale, TGF-β1 = transforming growth factor βeta 1; Group differences assessed with Fisher’s Exact Test and Mann-Whitney U test. Effect size estimate for Mann-Whitney U test: r = z/√N.

Peripheral BDNF levels were detected in 25 out of 33 samples and cholesterol levels were available for 32 out of 33 participants; otherwise, the sample size for variables was 33. Participants with IBS and HC did not differ when grouped into age and weight categorizations as previously described (Fisher’s Exact Test for significance: p = 1.00, p = .469, respectively). Participants with IBS did, however, display significantly higher levels of estradiol than did HC participants (p = .027), with a corresponding effect size of .384, representing a medium sized effect (Cohen, 1977).

Associations and Relationships Among Study Variables

Similarities and differences were noted between participants with IBS and HC when evaluating associations among biological and psychological variables, as shown in Table 2. Significant associations are displayed with both unadjusted and adjusted p values, to correct for the 14 comparisons conducted. For instance, significant, positive associations were noted for both groups among age, BMI, cholesterol, and leptin. Further similarities include positive associations between BDNF and TGF-β1, and between PSS and CES-D scores. Differences between groups include a significant positive association between BDNF and progesterone in HC, whereas IBS participants displayed a negative association.

Table 2.

Significant Associations Between Study Variables (Spearman’s ρ).

rs (p) ACTH BMI FSH Leptin Progesterone PSS TGF-β1
Age—Total . .620 (.001) . .512 (.002) . .350 (.046) .
HC . .596 (.004) . . −.442 (.045) . .
IBS . .622 (.031) . .657 (.020) . .595 (.041) .
BDNF—Total . . . . . .882 (.001)
HC .685 (.003) . −.763 (.001) . .623 (.010) . .779 (.001)
IBS . . . . −.723 (.028) . .883 (.002)
BMI—Total . . . .905 (.001) . . .
HC . . . .861 (.001) . . .
IBS . . . .923 (.001) . . −.629 (.028)
CES-D—Total . . . . . .627 (.001) .
HC . . . . . .544 (.011) .
IBS . . . . . .621 (.031) .
Cholesterol—Total . .547 (.001) . .537 (.002) −.410 (.020) . .
HC . .494 (.027) . .509 (.022) −.550 (.012) . .
IBS . .685 (.014) . .692 (.013) . . .
Estradiol—Total .413 (.017) . −.356 (.042) . .359 (.040) . .
HC .583 (.006) . . . .475 (.029) . .
IBS . . −.651 (.022) . . . .
FSH—Total −.377 (.031) . . . −.444 (.010) . .
HC −.550 (.010) . . . −.503 (.020) . .
LH—Total . . . . . . .
HC . . . . . . .
IBS . . . −.666 (.018) . . .
TGF-β1—Total . . . . . . .
HC .479 (.028) . −.494 (.023) . . . .
IBS . −.629 (.028) . −.587 (.045) . . .
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Note. HC = healthy controls, IBS = irritable bowel syndrome, ACTH = adrenocorticotropic hormone, BDNF = brain-derived neurotrophic factor, BMI = body mass index, CES-D = Center for Epidemiological Studies Depression Scale, FSH = follicular stimulating hormone, LH = luteinizing hormone, PSS = Perceived Stress Scale, TGF-β1 = transforming growth factor βeta 1. Associations in bold significant after adjusting for multiple comparisons using Bonferroni correction: p = .05/14 = .004.

Different patterns were also detected among sex hormones between groups. An overall positive association between estradiol and progesterone remained significant only in HC once separating by group, whereas an overall negative association between estradiol and FSH remained significant only in participants with IBS. Negative relationships between BDNF and FSH, and between TGF-β1 and FSH were detected for HC, whereas negative associations were noted for participants with IBS between TGF-β1 and leptin, and between leptin and LH. Lastly, associations with markers of the stress response were significant only in HC, who displayed a positive association between ACTH and estradiol, ACTH and BDNF, and a negative association between ACTH and FSH.

Multivariable linear regression was used to evaluate relationships among study variables of interest, and to assess whether these relationships varied between participants with IBS and HC. Models were created between study variables while adjusting for cholesterol, age, and weight (grouped as previously described), and relationships were evaluated for effect moderation by IBS diagnosis. Looking at the variables under inquiry, the relationship between log (CES-D) and log (estradiol) appeared to vary by IBS status, and a significant interaction was noted between IBS status and log (estradiol), p = 0.019, as shown in Table 3. Estradiol was found to be negatively associated with CES-D scores for HC (estradiol coefficient of −0.33), whereas estradiol was positively associated with CES-D scores for participants with IBS (estradiol coefficient of 0.92).

Table 3.

Relationship Between Log10 (CES-D scores) and Log10 (Estradiol).

Model B SE (B) β t p
Intercept 1.537 1.933 .795 .434
Age Category −.336 .167 −.512 −2.007 .056
log10 (Cholesterol) −.140 .847 −.031 −.165 .870
Weight Category .634 .171 .959 3.703 .001
log10 (Estradiol) −.326 .217 −.280 −1.500 .146
IBS diagnosis −2.287 .952 −3.378 −2.403 .024
Int log 10 (Est) × IBS 1.243 .497 3.562 2.502 .019
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Note. R2 = .43; p = .021. Model adjusted for age, cholesterol & weight. Bold face values denote the significant values.

Discussion

The purpose of this exploratory pilot study was to evaluate sex hormones and other modulators of the BGA in female participants with IBS, by examining patterns of associations among biological and psychological indices in comparison to HC. We investigated markers of the HPA and HPG axes, as well as BDNF, leptin, and TGF-β1, given their relevance to GI symptoms and mood, and prior evidence of association with IBS. Participants with IBS displayed significantly higher levels of estradiol than did HC, although further significant differences were not detected in the variables under inquiry. Given that estrogen can modulate pain (Craft, 2007), this finding bears further investigation across the menstrual cycle in females with IBS. Differing relationships among hormones between groups (including estradiol, progesterone, and FSH), also encourages further inquiry as to the role of sex hormones in IBS symptomatology, and possible alterations in normal feedback mechanisms along the HPG axis. Preclinical studies demonstrate the significance of early-life stress and estrous cycle in sensitivity to visceral pain (Moloney et al., 2016), and it has been noted that declining or low ovarian hormones may exacerbate symptomatology in patients with IBS (Heitkemper & Chang, 2009). Reliance upon the self-report of menstrual cycle phase versus objective hormone level measurement, however, has impeded our understanding of hormonal influence on chronic pain conditions (Hassan et al., 2014).

Modeling relationships among study variables provides further support for the role of sex hormones in IBS symptomatology, as an interaction effect was noted for IBS grouping between the log (estradiol) and log (CES-D), after adjusting for age, weight, and cholesterol. Although this effect may not translate into a clinically meaningful difference, it encourages further inquiry into the relationship between sex hormones and depressive symptomatology in patients with IBS. Furthermore, the significant, positive association between age and scores on the PSS noted in IBS participants, but not in HC, urges further assessment of stress in females with IBS as they age, and the possible contribution of changes in hormone levels. Variations were also noted by participant group in associations between sex hormones and other modulators along the BGA. For instance, the association between BDNF and progesterone was positive for HC, yet negative for participants with IBS. Earlier research demonstrates a positive correlation between BDNF and progesterone in fertile females across the menstrual cycle (Begliuomini et al., 2007). As progesterone regulates the expression of BDNF (Pluchino et al., 2013) and is associated with anti-depressant effects (Sovijit et al., 2019), differences in this relationship may bear relevance to higher scores on the CES-D (albeit not reaching statistical significance), as noted for participants with IBS.

This investigation reports expected relationships for both participant groups in study variables related to age, BMI, cholesterol, and leptin. An earlier study evaluating leptin and LH during the early follicular phase, reports a synchronicity of serum levels in normal cycling females (Sir-Petermann et al., 1999). Although the positive association between leptin and LH in HC did not reach significance, these variables were significantly associated in participants with IBS, albeit in a negative direction. To ascertain whether variations of this relationship in participants with IBS relate to alterations in the HPG circuitry, quantification of hormones must be performed across the menstrual cycle. Further differences between groups include the negative association between BMI and TGF-β1 for participants with IBS, not found for HC, which may relate to underlying metabolic/inflammatory processes. Although not reaching statistical significance, participants with IBS were noted to display lower levels of BDNF than HC; this is in contrast to a larger investigation which reports significantly higher levels of peripheral BDNF in IBS-D participants (with increased small intestinal permeability) in comparison with HC (Russo et al., 2018).

Such divergent findings highlight 2 notable limitations of this pilot investigation: sample size and predominant subtype of IBS participants (IBS-C). Although admittedly underpowered to detect group differences and unable to account for subtype in assessments of IBS, our findings discern biological trends that can be investigated for relevance on a larger scale. Further limitations of this investigation include its cross-sectional nature and that participants were scheduled during days 3–10 of their menstrual cycle. Although this scheduling was purposeful in the parent study’s design to minimize hormonal influence, it restricts our ability to evaluate its potential effects. Despite these noted limitations, this pilot study does report IBS participants to display significantly higher levels of estradiol than HC, differential patterns of biological and psychological indices between groups, and supports further investigations of the role of sex hormones, BDNF, leptin, and TGF-β1 in the disorder of IBS. Future research endeavors should conduct longitudinal quantification of sex hormones across the menstrual cycle, coupled with subjective symptom assessment, to facilitate insight on pathophysiology and the female sex bias in IBS. Such knowledge will promote the design of targeted interventions to improve the brain-gut connection, and optimize outcomes for patients with IBS.

Acknowledgments

Thanks are extended to Drs. Bruce McEwen (in memoriam) and Daniel Mucida of The Rockefeller University, Dr. Peter Schmidt of the National Institute of Mental Health (NIH), Dr. Pamela Tamez and Ms. Shavonne Pocock of the National Institute of Nursing Research (NIH), and Ms. Cheryl Johnson of the Clinical Center (NIH) for their input and assistance surrounding this research.

Footnotes

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: The authors would like to acknowledge funding from The Rockefeller University, Heilbrunn Nurse Scholar Award (KRW), U.S. Department of Health and Human Services, National Institutes of Health (NIH), National Institute of Nursing Research, Division of Intramural Research (Training Awards: KRW, JMR, CMB, KB; ZIANR000018: WAH). KRW received support from the National Institute of Neurological Diseases and Stroke while at Johns Hopkins University (T32NS070201), and would like to acknowledge Johns Hopkins Institute for Clinical and Translational Research for statistical analysis, funded in part by the National Center for Advancing Translational Sciences (UL1TR001079).

ORCID iDs: Kristen R. Weaver Inline graphic https://orcid.org/0000-0002-8757-8758

Wendy A. Henderson Inline graphic https://orcid.org/0000-0003-3924-7118

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