ArticlePublisher preview availableLiterature Review

Stressing the need for validated measures of cortisol in HIV research: A scoping review

HIV Medicine

March 2022
23(8)

DOI:10.1111/hiv.13272

Authors:

Shayda A Swann

University of British Columbia

Hélène C F Côté

University of British Columbia

Melanie Murray

University of British Columbia

Objectives People living with HIV experience numerous endocrine abnormalities and psychosocial stressors. However, interactions between HIV, cortisol levels, and health outcomes have not been well described among people living with HIV on effective therapy. Furthermore, methods for measuring cortisol are disparate across studies. We describe the literature reporting cortisol levels in people living with HIV, describe methods to measure cortisol, and explore how this relates to health outcomes. Methods We searched the PubMed database for articles published in the past 20 years regarding HIV and cortisol with ≥50% of participants on antiretroviral therapies. Articles included observational, case‐control, cross‐sectional, and randomized controlled trials analyzing cortisol by any method. Studies were excluded if abnormal cortisol was due to medications or other infections. Variables were extracted from selected studies and their quality was assessed using the Newcastle–Ottawa Scale. Results In total, 19 articles were selected and included, covering the prevalence of abnormal cortisol (n = 4), exercise (n = 4), metabolic syndrome and/or cardiovascular disease (n = 2), mental health and cognition (n = 9), and sex/gender (n = 6). Cortisol was measured in serum (n = 7), saliva (n = 8), urine (n = 2), and hair (n = 3) specimens. Comparisons between people with and without HIV were inconsistent, with some evidence that people with HIV have increased rates of hypocortisolism. Depression and cognitive decline may be associated with cortisol excess, whereas anxiety and metabolic disease may be related to low cortisol; more data are needed to confirm these relationships. Conclusions Data on cortisol levels in the era of antiretroviral therapy remain sparse. Future studies should include controls without HIV, appropriately timed sample collection, and consideration of sex/gender and psychosocial factors.

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wileyonlinelibrary.com/journal/hiv HIV Medicine. 2022;23:880–894.

Received: 6 October 2021

Accepted: 1 February 2022

DOI: 10.1111/hiv.13272

ORIGINAL ARTICLE

Stressing the need for validated measures of cortisol in HIV

research: A scoping review

Shayda A.Swann1,2

Elizabeth M.King2,3

Hélène C. F.Côté1,2,4,5

MelanieC.M.Murray1,2,3,6

1Department of Experimental

Medicine, University of British

Columbia, Vancouver, British

Columbia, Canada

2Women’s Health Research Institute,

Vancouver, British Columbia, Canada

3Department of Medicine, University

of British Columbia, Vancouver, British

Columbia, Canada

4Department of Pathology and

Laboratory Medicine, University of

British Columbia, Vancouver, British

Columbia, Canada

5Centre for Blood Research, University

of British Columbia, Vancouver, British

Columbia, Canada

6Oak Tree Clinic, BC Women’s Hospital

and Health Centre, Vancouver, British

Columbia, Canada

Correspondence

Melanie C. M. Murray, E600B— 4500

Oak Street, Vancouver, BC V6H 3N1,

Canada.

Email: Melanie.Murray@cw.bc.ca

Funding information

Canadian Institutes of Health Research;

University of British Columbia;

Michael Smith Foundation for Health

Research; Canadian HIV Trials

Network, Canadian Institutes of Health

Research

Abstract

Objectives: People living with HIV experience numerous endocrine abnormali-

ties and psychosocial stressors. However, interactions between HIV, cortisol lev-

els, and health outcomes have not been well described among people living with

HIV on effective therapy. Furthermore, methods for measuring cortisol are dis-

parate across studies. We describe the literature reporting cortisol levels in peo-

ple living with HIV, describe methods to measure cortisol, and explore how this

relates to health outcomes.

Methods: We searched the PubMed database for articles published in the past

20 years regarding HIV and cortisol with ≥50% of participants on antiretrovi-

ral therapies. Articles included observational, case- control, cross- sectional, and

randomized controlled trials analyzing cortisol by any method. Studies were ex-

cluded if abnormal cortisol was due to medications or other infections. Variables

were extracted from selected studies and their quality was assessed using the

Newcastle– Ottawa Scale.

Results: In total, 19 articles were selected and included, covering the prevalence

of abnormal cortisol (n = 4), exercise (n=4), metabolic syndrome and/or car-

diovascular disease (n=2), mental health and cognition (n=9), and sex/gender

(n=6). Cortisol was measured in serum (n=7), saliva (n=8), urine (n=2), and

hair (n=3) specimens. Comparisons between people with and without HIV were

inconsistent, with some evidence that people with HIV have increased rates of

hypocortisolism. Depression and cognitive decline may be associated with corti-

sol excess, whereas anxiety and metabolic disease may be related to low cortisol;

more data are needed to confirm these relationships.

Conclusions: Data on cortisol levels in the era of antiretroviral therapy remain

sparse. Future studies should include controls without HIV, appropriately timed

sample collection, and consideration of sex/gender and psychosocial factors.

KEYWORDS

adrenal, cortisol, HIV, review, stress

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Association Between Mother-Infant Hair Cortisol Levels, Perinatal Stressors, and Adverse Birth Outcomes Among Kenyan Mother-Infant Pairs

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Dec 2023

Background: Few data on maternal-infant hair cortisol are available from HIV high-burden settings. We evaluated maternal hair cortisol and its relationship with infant hair cortisol, perinatal stressors, and pregnancy outcomes in Kenya. Materials and Methods: We analyzed data from an HIV prevention trial (NCT03070600). Pregnant women without HIV were enrolled and followed through 9 months postpartum. We utilized hair samples collected at 6 weeks postpartum from mother-infant pairs to quantify hair cortisol concentrations (HCC) reflecting cortisol levels over the prior ∼3 months. HCC was measured by enzyme immunoassay. We tested whether mean maternal HCC was associated with infant HCC, stressors, and/or birth outcomes using linear regression. Results: Overall, 153 women had HCC available at 6 weeks postpartum. Median maternal age was 25 years (Interquartile range [IQR] 22–30), median completed education was 12 years (IQR: 8–12), and 95% were married. Median birthweight was 3.4 kilograms (IQR: 3.1–3.7), 13% of women experienced preterm birth (PTB), and 2% of infants had low birthweight (LBW); 11% were small-for-gestational age (SGA). Median maternal HCC was 12.0 pg/mg (IQR: 6.3–20.4); and median infant HCC was 10.4 pg/mg (IQR: 5.5–23.7). Infant HCC was correlated with maternal HCC (r = 0.498, p < 0.001). Stressors associated with maternal HCC (p < 0.05) included having a partner living with HIV or of unknown HIV status, relationship instability, and having high behavioral risk for HIV. Maternal HCC was not significantly associated with PTB, LBW, or SGA. Conclusion: In conclusion, peripartum maternal HCC was correlated with infant HCC and associated with experiencing HIV acquisition-related stressors.

Low Levels of Cortisol are Associated with HIV infection in Older People: A Hormonal Substudy in the OVER50 Cohort

Article

Aug 2024
CURR HIV RES

Introduction People with the human immunodeficiency virus (PWH) who were diagnosed long ago are more prone to age-related conditions and comorbidities than the general population. We hypothesized that older PWH have endocrine abnormalities that may influence the patient’s health status. Methods Mean hormonal values across the thyrotropic, somatotropic, corticotropic, and gonadal axis, and percentage of subjects with abnormal values, were compared between PWH aged ≥50 years (n=30) and people without HIV (n=30) (Over50 cohort). Clinical factors were also analyzed as independent variables. Results PWH had a higher prevalence of comorbidities (36.67% PWH and 20.69% controls had ≥3 comorbidities). Male PWH exhibited lower estradiol levels than male controls (29.75±7.68 pg/mL vs. 35.45±10.04 pg/mL; p=0.0041). Abnormal concentrations of testosterone were found in 35% of male PWH compared to 55% of male controls (mostly above reference values). Cortisol levels were significantly lower among PWH (9.97±4.33 μg/dL vs. 13.56±3.39 μg/dL; p=0.002); 16.6% of PWH exhibited abnormally low levels (<5 μg/dL), compared to 0% of controls, and 3 PWH met criteria for a definitive diagnosis of adrenal insufficiency (<3.6 μg/dL). For the somatotropic axis, growth hormone (GH) levels were significantly lower in male PWH than in controls (p=0.0394). No significant differences were found in relation to the thyroid axis. Conclusion Hormones are generally similar between the chronic PWH who are receiving ART treatment and the general control population, except for cortisol in both sexes and testosterone and estradiol in men. Some special attention should be given to cortisol in PWH due to a presumably higher risk of adrenal complications. Other Additional data such as a complete adrenal study, long-term adrenal clinical complications, and a higher population size should be considered in future prospective studies.

Hypertension and Metabolic Syndrome in Persons with HIV

Article

Full-text available

Sep 2020
Curr Hypertens Rep

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Acceptability and Feasibility of Hair and Salivary Biomarker Collection Among Multiethnic School-Age Children

Article

Full-text available

Jul 2020
MATERN CHILD HLTH J

Objective As noninvasive biological markers gain increasing popularity in pediatric research, it is critical to understand how study participants perceive these measures, especially among groups underrepresented in biobehavioral research, like children and people of color. The purpose of this study was to examine acceptability and feasibility of hair and salivary biomarker collection in an urban community sample of ethnically diverse children (age 4 to 10 years).Methods Ninety-seven mother–child dyads were recruited for a cross-sectional follow up study of the Minding the Baby® home visiting intervention. Children were Hispanic (63%), Black (34%), and multi-racial (3.1%). A conventional content analysis was conducted using two sources of data: (1) mothers’ responses to open-ended interview questions on their views and suggestions regarding biomarker collection, and (2) field notes recorded by investigators.ResultsForty-four percent of mothers reported biomarker-related questions or concerns, including questions about the purpose of biomarker testing, and concerns about cosmetic issues, child discomfort, and future use of biomarker data. Mothers also offered positive feedback and advice for collection. Issues affecting feasibility included children’s hair length and style, refusal to participate, and behavioral or developmental issues.Conclusions Hair and salivary biomarker collection was largely acceptable and feasible in this sample. Strategies for promoting ethical and sensitive biomarker collection include respectful explanations and parental involvement, creating a comfortable and safe environment for the child, flexible collection strategies, and attention to development, cultural preferences and perspectives.

Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis

Article

Full-text available

Apr 2020

Although results of animal research show that interactions between stress and sex hormones are implicated in the development of affective disorders in women, translation of these findings to patients has been scarce. As a basic step toward advancing this field of research, we analyzed findings of studies which reported circulating cortisol levels in healthy women in the follicular vs. luteal phase of the menstrual cycle. We deemed this analysis critical not only to advance our understanding of basic physiology, but also as an important contrast to the findings of future studies evaluating stress and sex hormones in women with affective disorders. We hypothesized that cortisol levels would be lower in the follicular phase based on the proposition that changes in levels of potent GABAergic neurosteroids, including allopregnanolone, during the menstrual cycle dynamically change in the opposite direction relative to cortisol levels. Implementing strict inclusion criteria, we compiled results of high-quality studies involving 778 study participants to derive a standardized mean difference between circulating cortisol levels in the follicular vs. luteal phase of the menstrual cycle. In line with our hypothesis, our meta-analysis found that women in the follicular phase had higher cortisol levels than women in the luteal phase, with an overall Hedges’ g of 0.13 (p<0.01) for the random effects model. No significant between-study difference was detected, with the level of heterogeneity in the small range. Furthermore, there was no evidence of publication bias. As cortisol regulation is a delicate process, we review some of the basic mechanisms by which progesterone, its potent metabolites, and estradiol regulate cortisol output and circulation to contribute to the net effect of higher cortisol in the follicular phase.

Low Neuroactive Steroids Identifies a Biological Subtype of Depression in Adults with Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy

Article

Full-text available

Mar 2020
J INFECT DIS

Background: The prevalence and mortality risk of depression in people with Human Immunodeficiency Virus (HIV)-infection (PWH) on antiretroviral therapy (ART) is higher than in the general population, yet biomarkers for therapeutic targeting are unknown. Here, we aimed to identify plasma metabolites associated with depressive symptoms in PWH on ART. Methods: This is a prospective study of ART-treated HIV-infected adults with or without depressive symptoms assessed using longitudinal Beck Depression Inventory scores. Plasma metabolite profiling was performed in two independent cohorts (total n=99) using liquid and gas chromatography and tandem mass spectrometry. Results: Participants with depressive symptoms had lower neuroactive steroids (dehydroepiandrosterone sulfate (DHEA-S), androstenediols, pregnenolone sulfate) compared to those without depressive symptoms. Cortisol/DHEA-S ratio, an indicator of hypothalamic-pituitary-adrenal axis imbalance, was associated with depressive symptoms (p<0.01) due to low DHEA-S, while cortisol was similar between groups. The odds of having depressive symptoms increased with higher cortisol/DHEA-S ratios [odds 2.5 per z-score, 95% confidence interval 1.3-4.7], independent of age and gender. Kynurenine to tryptophan ratio showed no significant associations. Conclusions: These findings suggest that altered neuroactive steroid metabolism may contribute to the pathophysiology of depression in ART-treated HIV-infected adults, representing a potential biological pathway for therapeutic targeting.

Perinatal Food Insecurity and Postpartum Psychosocial Stress are Positively Associated Among Kenyan Women of Mixed HIV Status

Article

Full-text available

Jun 2020
AIDS BEHAV

Stress and food insecurity (FI) are associated with poor perinatal and HIV outcomes. We hypothesized that FI would increase postpartum stress among women in Kenya, and that the impact would be greater in women with HIV. Among 371 pregnant women, we identified latent FI trajectories across the perinatal period, and estimated their association with postpartum stress. Stress metrics included the Perceived Stress Scale (PSS) and hair cortisol concentrations (HCC). We identified two FI trajectories: persistent moderate FI and persistent mild FI. Moderate FI (vs. mild) was associated with higher PSS; this association was stronger among HIV-negative women. We observed a trend towards higher HCC associated with moderate FI, which did not differ by HIV status. HCC and PSS were not correlated. In summary, moderate FI (vs. mild) was associated with increased stress. The lack of PSS–HCC correlation could reflect different physiological pathways. Interventions to mitigate FI could alleviate postpartum stress.

Combined Exercise Modulates Cortisol, Testosterone, and Immunoglobulin A Levels in Individuals Living With HIV/AIDS

Article

Full-text available

Sep 2019

Background: Combined exercise (CE) has been recommended for individuals living with HIV/AIDS (ILWHA) under antiretroviral therapy. However, depending on the intensity and duration, physical exercise may occasionally increase inflammatory parameters and reduce immunological responses that if not reversed, cause health injury specifically in this population. Information about immunological and hormonal responses after CE in ILWHA has not been completely elucidated. Therefore, the aim is to verify the acute effects of CE on cortisol, testosterone, immunoglobulin A, and pro-inflammatory and anti-inflammatory cytokines over 24 hours in ILWHA. Methods: Noninfected individuals and ILWHA undergone 5 sessions of CE prior to the acute assessment session. Seventy-two hours after the last session, the subjects were submitted to one session of CE (aerobic exercise: 25 min at 60-70% reserve heart rate and resistance exercise: 3 sets of 15 maximum repetitions of 6 exercises). Saliva samples were collected before, immediately, 6 and 24 hours after CE. Results: CE reduced cortisol (6 h: 2.54 [0.58] vs 0.65 [0.22] pg·mL-1; P = .02), increased testosterone (all moments) and immunoglobulin A levels (24 h: 255.3 [44.7] vs 349.2 [41.9] μm·mL-1; P = .01) without significant difference in cytokines levels in ILWHA. Conclusion: CE modulates cortisol, testosterone, and immunoglobulin A levels without the change in immunological parameters in ILWHA.

The Immune System in Cushing’s Syndrome

Article

May 2020
TRENDS ENDOCRIN MET

Cushing’s syndrome (CS), or chronic hypercortisolism, induces a variety of alterations in the immune system, often leading to severe clinical complications such as sepsis and opportunistic infections. Prolonged exposure to high levels of glucocorticoids (GC), changes in the circadian rhythm, and the comorbidities associated therewith all combine to cause profound changes in the immune profile of affected patients. While traditionally associated with generalized immune suppression, such changes actually comprise a much more complex scenario, sharing traits with chronic inflammatory disorders. Persistently increased levels of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα) and adipose tissue infiltration by immune cells lead to a chronic, nonresolving, inflammatory state. The combination of low-grade inflammation and selectively impaired immune response is thought to play a major role in the pathogenesis of clinical complications of CS, including diabetes, lipodystrophy, visceral adiposity, atherosclerosis, osteoporosis, and cognitive impairment. This dysregulation also explains rebound phenomena when CS is treated, involving new clinical complications sustained by an excessive immune response and autoimmunity. The aim of this review is to summarize the available evidence on the immune system in chronic hypercortisolism, while describing the main mechanisms of immune derangement and their role in the increased mortality and morbidity seen in this complex disease. A better understanding of immune system alterations in CS could help improve risk stratification, offer novel biomarkers, and provide the basis for more tailored therapies and post-remission follow-up.

Remitted depression and cognition in HIV: The role of cortisol and inflammation

Article

Feb 2020
PSYCHONEUROENDOCRINO

In major depressive disorder (MDD) and remitted MDD (rMDD) alterations in cortisol and inflammation are associated with cognitive difficulties, but these relationships have not been investigated in HIV. We used secondary data from a placebo-controlled, cross-over study of cognitive performance following a probe of the hypothalamic-pituitary-adrenal (HPA) axis (low dose hydrocortisone; LDH 10 mg) in 65 people with HIV (PWH; 36 women). Using placebo data, we examined sex-specific associations between two biomarkers - basal afternoon salivary cortisol and salivary inflammatory cytokines - cognition, and rMDD. Salivary cortisol and inflammatory biomarkers were sampled across the 5 -h study. The panel of inflammatory markers included interleukin (IL)-6, IL-8, IL-1β, tumor necrosis factor-(TNF)-α, CRP, interferon gamma-induced protein (IP-10), monocyte chemotactic protein (MCP)-1, monokine induced by interferon (MIG), matrix metalloproteinase MMP-9, and MMP-1. Learning, memory, attention/concentration, and executive function were assessed 30 min and 4 h after the placebo intervention; visuospatial ability was also assessed 30 min after the placebo intervention. For women but not men with HIV, basal cortisol concentrations were higher in rMDD versus noMDD groups, and related to poorer learning and memory. For men and women with HIV, basal inflammatory cytokines were higher in rMDD versus noMDD groups, but were negatively related to cognition independent of rMDD status. Cortisol and cytokines relate to cognition in PWH, but the associations depended on sex, rMDD status, and their interaction.

Comorbidity and polypharmacy among women living with HIV in British Columbia

Article

Aug 2019

Objective: To characterize comorbid disease and medication burden among women living with HIV (WLWH) in British Columbia (BC), Canada. Design: We examined baseline data from 267 WLWH and 276 HIV-negative females, ≥19 years, enrolled in the Children and Women: Antiretrovirals and Markers of Aging (CARMA) cohort. Methods: Self-reported demographic, medical condition, medication, vitamin, and substance exposure data were collected at baseline CARMA study visits. We considered conditions with appropriate concomitant medications to be "treated". Wilcoxon rank-sum and Fisher's exact tests compared continuous and categorical variables between WLWH and HIV-negative women. Number of diagnoses, prescribed medications (excluding HIV/antiretrovirals), vitamins, and prevalence of depression/anxiety/panic disorder were compared using negative binomial and logistic regressions for continuous and binary variables respectively. Results: WLWH were younger (median [IQR] 39.9 [33.6-46.9] vs 43.6 [31.8-54.6] years, p = 0.01), attained lower education (40.5% vs 69.6% college/university, p < 0.001), and more often currently smoked tobacco (47.9% vs 31.9%, p < 0.001), or had income <$15,000/year (49.0% vs 43.1%, p < 0.001). Although younger, and despite omitting HIV infection, WLWH had a greater number of diagnoses (IRR [95%CI] 1.58 [1.38-1.81], p <0.001), and more depression/anxiety/panic disorder versus controls (OR [95% CI], 1.86 [1.22-2.83], p = 0.004). Our model predicts that with mean BMI (26.3), WLWH and HIV-negative peers would have two comorbid diagnoses by age 30 and 60, respectively. Conclusions: WLWH living in BC have more comorbid illness earlier in life than their HIV-negative peers, and have very high rates of depression/anxiety/panic disorder. Addressing mental health and comorbid conditions is essential to improving health outcomes among WLWH.

Pathways to Health: an Examination of HIV-Related Stigma, Life Stressors, Depression, and Substance Use

Article

May 2019

Background Despite antiretroviral treatment (ART) being an efficacious treatment for HIV, essentially making it a chronic non-terminal illness, two related and frequent concerns for many people living with HIV/AIDS (PLWHA) continue to be HIV-related stigma and life stress. These two variables are frequently associated with depression, substance use, and poorer functional health. Studies to date have not fully examined the degree to which these constructs may be associated within one model, which could reveal a more nuanced understanding of how HIV-related stigma and life stress affect functional health in PLWHA. Methods The current study employed hybrid structural equation modeling to examine the interconnectedness and potential indirect relationships of HIV-related stigma and life stress to worse health through substance use and depression, controlling for ART adherence and age. Participants were 240 HIV-infected individuals who completed a biopsychosocial assessment battery upon screening for an RCT on treating depression in those infected with HIV. Results Both HIV-related stigma and stressful life events were directly related to depression, and depression was directly related to health. There were significant indirect effects from stigma and stress to health via depression. There were no significant effects involving substance use. Conclusion It is important to continue to develop ways to address stigma, stressful life events, and their effects on distress in those living with HIV. Expanding our knowledge of disease progression risk factors beyond ART adherence is important to be able to design adjuvant interventions, particularly because treatment means that people living with HIV have markedly improved life expectancy and that successful treatment means that HIV is not transmittable to others.

Stressing the need for validated measures of cortisol in HIV research: A scoping review

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