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Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression.

ABSTRACT: The incidence of depression is approximately 2-fold greater in women than men but the biological mechanisms underlying this phenomenon remain unclear. One potential mechanism that has been understudied is immune function, which is modulated by sex hormones and differs considerably between males and females. The immune-regulating kynurenine pathway previously has been implicated in the pathogenesis of mood disorders. In particular, a decreased ratio of neuroprotective (kynurenic acid; KynA) to neurotoxic (3-hydroxykynurenine; 3HK and quinolinic acid; QA) kynurenine pathway metabolites has been reported in several mood disorder subtypes. Yet there is a paucity of research investigating sex differences in the kynurenine pathway in the context of depression. Similarly, oral contraceptive (OC) use has been shown to be a risk factor for depression but to our knowledge this epidemiological relationship has not been considered within the framework of immune dysfunction. Here, we compared the concentrations of c-reactive protein (CRP) and kynurenine pathway metabolites in a combined sample of subjects with major depressive disorder (MDD), bipolar disorder (BD), and healthy controls (HC) comprising 130 men and 350 women. CRP was measured in a CLIA-certified hospital laboratory. Kynurenine metabolites were quantified using high performance liquid chromatography with tandem mass spectrometry. Estradiol and progesterone were quantified with the Mesoscale Discovery (MSD) platform. After controlling for diagnosis, age, sex, BMI, analysis batch, and self-reported childhood trauma we found that women had significantly lower KynA/3HK and KynA/QA ratios than men, and that these results were driven by a decrease in KynA. There was no significant difference between males and females in the concentration of CRP. Further, women taking OC showed significantly higher levels of CRP and lower ratios of KynA/3HK and KynA/QA compared with women on no form of contraception. Moreover, among women using OC, progesterone concentrations were positively correlated with KynA, KynA/3HK, and KynA/QA. Although preliminary, our results indicate that on average, healthy women show the same pattern of kynurenine pathway metabolism as that observed in subjects with depression. This finding raises the possibility that a reduction in KynA concentrations in women may constitute a vulnerability factor that partly explains the higher incidence of depression in females. Further, the significant association between OC use and reduced KynA as well as increased CRP, could conceivably partially account for the epidemiological association between OC use and depression. Nonetheless, because of the cross-sectional nature of this study, these hypotheses need to be more rigorously tested with longitudinal designs and/or large epidemiological studies.

SUBMITTER: Meier TB

PROVIDER: S-EPMC5696064 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression.

Meier Timothy B TB Drevets Wayne C WC Teague T Kent TK Wurfel Brent E BE Mueller Sven C SC Bodurka Jerzy J Dantzer Robert R Savitz Jonathan J

Brain, behavior, and immunity 20170901

The incidence of depression is approximately 2-fold greater in women than men but the biological mechanisms underlying this phenomenon remain unclear. One potential mechanism that has been understudied is immune function, which is modulated by sex hormones and differs considerably between males and females. The immune-regulating kynurenine pathway previously has been implicated in the pathogenesis of mood disorders. In particular, a decreased ratio of neuroprotective (kynurenic acid; KynA) to ne ...[more]

PMID: 28867283

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Project description:BackgroundVenous thromboembolism (VTE) is a complex multifactorial disease influenced by genetic and environmental risk factors. An example for the latter is the regular use of combined oral contraceptives (CC), which increases the risk to develop VTE by 3 to 7 fold, depending on estrogen dosage and the type of progestin present in the pill. One out of 1'000 women using CC develops thrombosis, often with life-long consequences; a risk assessment is therefore necessary prior to such treatment. Currently known clinical risk factors associated with VTE development in general are routinely checked by medical doctors, however they are far from being sufficient for risk prediction, even when combined with genetic tests for Factor V Leiden and Factor II G20210A variants. Thus, clinical and notably genetic risk factors specific to the development of thrombosis associated with the use of CC in particular should be identified.Methods and findingsStep-wise (logistic) model selection was applied to a population of 1622 women using CC, half of whom (794) had developed a thromboembolic event while using contraceptives. 46 polymorphisms and clinical parameters were tested in the model selection and a specific combination of 4 clinical risk factors and 9 polymorphisms were identified. Among the 9 polymorphisms, there are two novel genetic polymorphisms (rs1799853 and rs4379368) that had not been previously associated with the development of thromboembolic event. This new prediction model outperforms (AUC 0.71, 95% CI 0.69-0.74) previously published models for general thromboembolic events in a cross-validation setting. Further validation in independent populations should be envisaged.ConclusionWe identified two new genetic variants associated to VTE development, as well as a robust prediction model to assess the risk of thrombosis for women using combined oral contraceptives. This model outperforms current medical practice as well as previously published models and is the first model specific to CC use.

Project description:ImportanceHormonal contraception has been linked to mood symptoms and the ability to recognize emotions after short periods of treatment, whereas the mental health of users of long-term hormonal contraceptives has had limited investigation.ObjectiveTo evaluate whether short-term hormonal withdrawal, which users of combined oral contraceptives (COCs) undergo once a month (pill pause), was associated with altered mood and emotional recognition in long-term users of COCs.Design, setting, and participantsThis case-control study included a community sample of individuals assigned female sex at birth who identified as women and used COC for 6 months or longer. The control group included women with natural menstrual cycles who otherwise fulfilled the same inclusion criteria. The study was conducted between April 2021 and June 2022 in Salzburg, Austria.ExposureCOC users and women with natural menstrual cycles were tested twice within a month, once during their active pill phase or luteal phase and once during their pill pause or menses.Main outcomes and measuresNegative affect, anxiety, and mental health problems were assessed during each session. The percentage increase in mental health symptoms was calculated during the pill pause compared with that during the active intake phase in COC users. How this change compared with mood fluctuations along the menstrual cycle in women with natural menstrual cycles was assessed.ResultsA total of 181 women aged 18 to 35 years (mean [SD] age, 22.7 [3.5] years) were included in the analysis (61 women with androgenic COC use, 59 with antiandrogenic COC use, 60 women with a menstrual cycle not taking COCs). COC users showed a 12.67% increase in negative affect (95% CI, 6.94%-18.39%), 7.42% increase in anxiety (95% CI, 3.43%-11.40%), and 23.61% increase in mental health symptoms (95% CI, 16.49%-30.73%; P < .001) during the pill pause compared with the active intake phase. The effect size of this change did not differ depending on progestin type (negative affect: F1,117 = 0.30, P = .59; state anxiety: F1,117 = 2.15, P = .15; mental health: F1,117 = .16, P = .69) or ethinylestradiol dose (negative affect: F1,57 = .99, P = .32; state anxiety: F1,57 = 2.30, P = .13; mental health: F1,57 = .14, P = .71) was comparable with mood changes along the menstrual cycle in women with natural cycles (negative affect: F2,175 = 0.13, P = .87; state anxiety: F2,175 = 0.14, P = .32; mental health: F2,175 = 0.65, P = .52). Mood worsening during the pill pause was more pronounced in women with higher baseline depression scores (negative affect increase of 17.95% [95% CI, 7.80%-28.10%] in COC users with higher trait depression [BDI >8]). Emotion recognition performance did not differ between active pill phase and pill pause.Conclusions and relevanceIn this case-control study of long-term COC users, withdrawal from contraceptive steroids during the pill pause was associated with adverse mental health symptoms similar to those experienced by women during menses with withdrawal from endogenous steroids. These results question the use of the pill pause from a mental health perspective. Long-term COC users may benefit more from the mood-stabilizing effects of COCs in cases of continuous intake.

Project description:AimResearch on the effect of oral contraceptive (OC) use on the risk of depression shows inconsistent findings, especially in adult OC users. One possible reason for this inconsistency is the omission of women who discontinue OCs due to adverse mood effects, leading to healthy user bias. To address this issue, we aim to estimate the risk of depression that is associated with the initiation of OCs as well as the effect of OC use on lifetime risk of depression.MethodsThis is a population-based cohort study based on data from 264,557 women from the UK Biobank. Incidence of depression was addressed via interviews, inpatient hospital or primary care data. The hazard ratio (HR) between OC use and incident depression was estimated by multivariable Cox regression with OC use as a time-varying exposure. To validate causality, we examined familial confounding in 7,354 sibling pairs.ResultsWe observed that the first 2 years of OC use were associated with a higher rate of depression compared to never users (HR = 1.71, 95% confidence interval [CI]: 1.55-1.88). Although the risk was not as pronounced beyond the first 2 years, ever OC use was still associated with an increased lifetime risk of depression (HR = 1.05, 95% CI: 1.01-1.09). Previous OC use were associated with a higher rate of depression compared to never users, with adolescent OC users driving the increased hazard (HR = 1.18, 95% CI: 1.12-1.25). No significant association were observed among adult OC users who had previously used OCs (HR = 1.00, 95% CI: 0.95-1.04). Notably, the sibling analysis provided further evidence for a causal effect of OC use on the risk of depression.ConclusionsOur findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life. Our results are consistent with a causal relationship between OC use and depression, as supported by the sibling analysis. This study highlights the importance of considering the healthy user bias as well as family-level confounding in studies of OC use and mental health outcomes. Physicians and patients should be aware of this potential risk when considering OCs, and individualized risk-benefit assessments should be conducted.

Project description:The present study evaluated cardiovagal baroreflex sensitivity (BRS) across the menstrual/pill cycle in naturally menstruating women (NAT women) and women using oral hormonal contraceptives (OCP women). In 21 NAT women (23 ± 4 years old) and 22 OCP women (23 ± 3 years old), cardiovagal BRS and circulating concentrations of estradiol and progesterone were evaluated during the lower hormone (early follicular/placebo pill) and higher hormone (late follicular to early luteal/active pill) phases. During the lower hormone phase, cardiovagal BRS up, down and mean gain were lower in NAT women (15.6 ± 8.3, 15.2 ± 6.1 and 15.1 ± 7.1 ms/mmHg) compared with OCP women (24.7 ± 9.4, 22.9 ± 8.0 and 23.0 ± 8.0 ms/mmHg) (P = 0.003, P = 0.002 and P = 0.003, respectively), and higher oestrogen (R2 = 0.15, P = 0.024), but not progesterone (R2 = 0.06, P = 0.18), concentrations were predictive of lower BRS mean gain. During the higher hormone phase, higher progesterone concentrations were predictive of lower BRS mean gain (R2 = 0.12, P = 0.024). A multivariate regression model revealed group (NAT or OCP) to be a significant predictor of cardiovagal BRS mean gain in the lower hormone phase when hormone concentrations were adjusted for (R2 = 0.36, P = 0.0044). The multivariate regression model was not significant during the higher hormone phase (P > 0.05). In summary, cardiovagal BRS is lower in NAT compared with OCP women during the lower hormone phase of the menstrual/pill cycle and might be associated with higher oestrogen concentrations. In contrast, during the higher hormone phase of the menstrual/OCP cycle, higher progesterone concentrations were predictive of lower cardiovagal BRS. NEW FINDINGS: What is the central question of this study? Does cardiovagal baroreflex sensitivity (BRS) differ between naturally menstruating women (NAT women) and women using oral contraceptives (OCP women)? What is the main finding and its importance? The main findings are as follows: (1) NAT women exhibit lower cardiovagal BRS than OCP women during the lower hormone phase of the menstrual or pill cycle; and (2) circulating oestrogen concentrations are significant predictors of cardiovagal BRS during the lower hormone phase, with higher oestrogen concentrations predicting lower BRS. The present data advance our understanding of the effect of endogenous ovarian hormones and OCP use on cardiovascular control mechanisms.

Project description:Previous studies indicate effects of oral contraceptive (OC) use on spatial and verbal cognition. However, a better understanding of the OC effects is still needed, including the differential effects of androgenic or anti-androgenic OC use and whether the possible impact persists beyond the OC use. We aim to investigate the associations of OC use duration with spatial and verbal cognition, differentiating between androgenic and anti-androgenic OC. Using functional magnetic resonance imaging (MRI), we scanned a group of 94 past and current OC-users in a single session. We grouped current OC users (N=53) and past OC users with a natural cycle (N=41) into androgenic and anti-androgenic user. Effects of OC use duration were observed for current use and after discontinuation. Duration of OC use was reflected only in verbal fluency performance but not navigation: The longer the current OC use, the less words were produced in the verbal fluency task. During navigation, deactivation in the caudate and postcentral gyrus was duration-dependent in current androgenic OC users. Only during the verbal fluency task, duration of previous OC use affects several brain parameters, including activation of the left putamen and connectivity between right-hemispheric language areas (i.e., right inferior frontal gyrus and right angular gyrus). The results regarding performance and brain activation point towards stronger organizational effects of OCs on verbal rather than spatial processing. Irrespective of the task, a duration-dependent connectivity between the hippocampus and various occipital areas was observed. This could suggest a shift in strategy or processing style with long-term contraceptive use during navigation/verbal fluency. The current findings suggest a key role of the progestogenic component of OCs in both tasks. The influence of OC use on verbal fluency remains even after discontinuation which further points out the importance of future studies on OC effects and their reversibility.

Project description:Background/Aims: Exposure toward positive emotional cues with - and without - reproductive significance plays a crucial role in daily life and regarding well-being as well as mental health. While possible adverse effects of oral contraceptive (OC) use on female mental and sexual health are widely discussed, neural processing of positive emotional stimuli has not been systematically investigated in association with OC use. Considering reported effects on mood, well-being and sexual function, and proposed associations with depression, it was hypothesized that OC users showed reduced neural reactivity toward positive and erotic emotional stimuli during early as well as later stages of emotional processing and also rated these stimuli as less pleasant and less arousing compared to naturally cycling (NC) women. Method: Sixty-two female subjects (29 NC and 33 OC) were assessed at three time points across the natural menstrual cycle and corresponding time points of the OC regimen. Early (early posterior negativity, EPN) and late (late positive potential, LPP) event-related potentials in reaction to positive, erotic and neutral stimuli were collected during an Emotional Picture Stroop Paradigm (EPSP). At each appointment, subjects provided saliva samples for analysis of gonadal steroid concentration. Valence and arousal ratings were collected at the last appointment. Results: Oral contraceptive users had significantly lower endogenous estradiol and progesterone concentrations compared to NC women. No significant group differences in either subjective stimulus evaluations or neural reactivity toward positive and erotic emotional stimuli were observed. For the OC group, LPP amplitudes in reaction to erotic vs. neutral pictures differed significantly between measurement times across the OC regimen. Discussion: In this study, no evidence regarding alterations of neural reactivity toward positive and erotic stimuli in OC users compared to NC was found. Possible confounding factors and lines for future research are elaborated and discussed.

Project description:Rationale & objectivePregnancy in females with kidney disease is not uncommon and is associated with adverse maternal and fetal outcomes. The use of contraception in females with chronic kidney disease remains low. We sought to describe the perspectives of female patients with advanced chronic kidney disease on the use of contraception.Study designQualitative study.Setting & participantsWe conducted 5 focus group interviews involving 16 adult female patients with advanced chronic kidney disease (n = 3 nondialysis nontransplant chronic kidney disease, n = 9 kidney transplant, and n = 4 kidney failure receiving dialysis) in the United States, following which thematic saturation was reached.Analytical approachInterview transcripts were analyzed thematically.ResultsWe identified the following 5 themes: 1) variable knowledge regarding reproductive health with kidney disease, 2) inadequate counseling about contraceptive use, 3) lack of interdisciplinary coordination regarding contraceptive use, 4) insufficient educational resources available to guide the contraceptive discussion, and 5) need for research to better understand reproductive needs in females with kidney disease.LimitationsPatients were from a single center in the United States, and the study is limited by the transferability of findings to other settings.ConclusionsPatients with chronic kidney disease report emotional challenges with reproductive health, lack of counseling and care coordination, and insufficient resources for contraceptive use. Strategies to strengthen these factors may improve the quality of reproductive care and increase contraceptive use for females with chronic kidney disease.Plain-language summaryPregnancy in females with kidney disease is common and associated with a higher risk of adverse maternal and fetal outcomes, but the use of contraception remains low. Little is known about female patients' experiences in contraceptive use that may contribute to low contraceptive use in this high-risk population. In the present study using focus group interviews, patients with chronic kidney disease reported emotional challenges with reproductive health, lack of counseling and care coordination, and insufficient resources for contraceptive use. Interventions are needed to strengthen these factors to improve the quality of reproductive care and increase contraceptive use for females with chronic kidney disease.

Dataset Information

Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression.

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Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression.

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