Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.

PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

The link between daily affective complexity and anxiety is altered by oral contraceptive use.

Affective complexity - the unique ways in which individuals' emotions covary and differentiate - is an important aspect of internalizing problems. For instance, daily affective complexity has been linked to anxiety increases in women and to decreases in men. The mechanisms underlying this gender difference have not been widely investigated, but a role for ovarian hormones is likely. Research on oral contraceptives (OCs) provides promising insights into such mechanisms, as OCs suppress endogenous ovarian hormone production and vary in exogenous hormone formulations. Thus, the goal of this study was to examine links between daily affective complexity and internalizing problems in OC users (n = 84), focusing on dimensionally-assessed anxiety, and to investigate whether the links varied by pill formulation. Affective complexity was operationalized as number of factors for each person, as estimated by p-technique (i.e., person-specific factor analysis) of 75-day intensive longitudinal data. There was not a relation between affective complexity and anxiety in OC users, and this did not depend on OC pill formulation (i.e., estrogenic, progestational, or androgenic activities). Thus, OC use may blunt the relation between affective complexity and anxiety, as OC users had a relation in between the established positive relation for naturally cycling women and the inverse for men (despite a similar range of factors). Findings are consistent with a growing literature showing that OC use modulates stress and anxiety-linked processes, and suggest that gendered mechanisms underlying the relation between affective complexity and anxiety may be suppressed along with ovarian hormones in OC users.

Comparison of the cytokine responses to acute strength exercise between oral contraceptive users and naturally cycling women.

PURPOSE: Cytokines are released as part of an inflammatory reaction in response to strength exercise to initiate muscle repair and morphological adaptations. Whether hormonal fluctuations induced by the menstrual cycle or oral contraceptives affect inflammatory responses to strength exercise remains unknown. Therefore, we aimed to compare the response of cytokines after acute strength exercise in naturally menstruating women and oral contraceptive users. METHODS: Naturally menstruating women (MC, n = 13, 24 ± 4 years, weekly strength training: 4.3 ± 1.7 h) and women using a monophasic combined pill (> 9 months) (OC, n = 8, 22 ± 3 years, weekly strength training: 4.5 ± 1.9 h) were recruited. A one-repetition-maximum (1RM) test and strength exercise in the squat (4 × 10 repetitions, 70%1RM) was performed in the early follicular phase or pill free interval. Concentrations of oestradiol, IL-1ß, IL-1ra, IL-6, IL-8, and IL-10 were assessed before (pre), directly after (post) and 24 h after (post24) strength exercise. RESULTS: IL-1ra increased from pre to post (+ 51.1 ± 59.4%, p = 0.189) and statistically decreased from post to post24 (- 20.5 ± 13.5%, p = 0.011) only in OC. Additionally, IL-1ß statistically decreased from post to post24 (- 39.6 ± 23.0%, p = 0.044) only in OC. There was an interaction effect for IL-1ß (p = 0.038) and concentrations were statistically decreased at post24 in OC compared to MC (p = 0.05). IL-8 increased across both groups from post to post24 (+ 66.6 ± 96.3%, p = 0.004). CONCLUSION: We showed a differential regulation of IL-1ß and IL-1ra between OC users in the pill-free interval and naturally cycling women 24 h after strength exercise, while there was no effect on other cytokines. Whether this is associated with previously shown compromised morphological adaptations remains to be investigated.

Effects of oral contraceptives on intrusive memories: a secondary analysis of two studies using the trauma film paradigm in healthy women.

Background: Women are more likely to develop post-traumatic stress disorder (PTSD) than men. Recent research suggests an impact of oral contraceptive (OC) intake on PTSD and intrusive memories, a hallmark symptom of PTSD. Although a majority of women use OCs at some point in their lives, the effects on PTSD pathogenesis are only poorly understood.Objective: In the current paper, we aimed to investigate the impact of OC intake on the acquisition and consolidation of intrusive memories in healthy women after watching a trauma film paradigm.Methods: We performed a secondary analysis of a pooled dataset (N = 437) of two previously conducted and published studies investigating the effect of oxytocin on the development of intrusive memories.Results: Women taking OCs showed an attenuated decline of intrusive memories over time after having watched the trauma film compared to naturally cycling women (F(2.75, 1167) = 3.79, p = .03, ηp2 = .01).Conclusion: These findings indicate that the intake of OCs is associated with the development of intrusive memories after a trauma film paradigm. This indication emphasizes the need to further investigate the complex impact of OCs and gonadal hormones on fear learning processes and PTSD.

The objective of the current study was to analyze the effect of oral contraceptives on the development of intrusive memories after a trauma film paradigm by conducting a secondary analysis of previously published data.Women taking oral contraceptives show an attenuated decline of intrusive memories after watching a trauma film paradigm compared to naturally cycling women in the luteal phase.Women using oral contraceptives show higher basal saliva cortisol levels.

Trunk variability and local dynamic stability during gait after generalized fatigue induced by incremental exercise test in young women in different phases of the menstrual cycle.

Purpose: The purpose of this study was to identify how generalized fatigue along with hormonal changes throughout the menstrual cycle affects trunk variability and local dynamic stability during gait. Methods: General fatigue was induced by an incremental test on a treadmill, and the menstrual cycle was divided into three phases: follicular, ovulatory, and luteal. Twenty-six healthy, young volunteers (aged 18 to 28 years) who did not use oral contraceptives or other hormonal drugs with a regular menstrual cycle participated in the study. They walked on the treadmill for 4 min at the preferred speed, before the incremental test, followed by four sets of 4 min alternating between walking, also at preferred speed, and resting. From trunk kinematic data, the following were extracted: the mean of the standard deviation along strides, as a measure of variability, and the maximum Lyapunov exponent, as a measure of local dynamic stability (LDS). Results: After the incremental test, variability increased, and LDS decreased. However, they showed a tendency to return to the initial value faster in women compared to previous results for men. In the follicular phase, which has less hormonal release, the volunteers had an almost complete recovery in LDS soon after the first rest interval, suggesting that female hormones can interfere with fatigue recovery. Nevertheless, concerning the LDS, it was significantly lower in the luteal phase than in the follicular phase. Conclusion: Women that are not taking oral contraceptives should be aware that they are susceptible to increased gait instabilities in the pre-menstrual phase after strenuous activities.

Improving menstrual health literacy in sport.

Menstrual health represents a state of complete physical, mental, and social well-being in relation to a woman's menstrual cycle. From a health literacy perspective, knowledge acquisition and expertise are dependent upon the degree to which an individual can find, access, understand, critically analyse, and apply health information. Therefore, menstrual health literacy can be used to describe the state of knowledge acquisition and application specific to menstrual health-related issues. Menstrual health literacy is low among female athletes, their coaches, and practitioners, and few evidence-informed education or implementation strategies exist to improve menstrual health literacy in sport. Moreover, athletes seldom discuss their menstrual cycles or hormonal contraceptive use with their coaches, despite experiencing menstrual symptoms and/or disturbances and perceiving their menstrual cycles/hormonal contraceptive use to affect performance. Barriers to communication about menstrual cycle- and hormonal contraceptive-related topics include a perceived lack of knowledge among athletes, coaches, and practitioners, concerns about how conversations on these issues will affect interpersonal relationships, and a lack of formal and informal discussion forums. Whilst evidence relating to the effects of the menstrual cycle phase and hormonal contraceptive use on training and performance is currently limited, with existing studies often lacking methodological rigour, impactful steps can still be made to support female athletes. This cornerstone review highlights the current state of menstrual health literacy among athletes, coaches, and practitioners, and provides recommendations for improving menstrual health literacy in sport.

Adrenocorticotropic hormone secretion in response to anticipatory stress and venepuncture: The role of menstrual phase and oral contraceptive use.

INTRODUCTION: Oral contraceptives (OCs) are primarily known for their effects on the reproductive system, but they can also impact the hypothalamic-pituitary-adrenal (HPA) axis. The present study aimed to compare plasma adrenocorticotropic hormone (ACTH) responses to the anticipatory stress of participating in a scientific experiment and venepuncture in OC users versus naturally cycling (NC) women, with a focus on variations throughout the menstrual cycle. METHODS: We recruited 131 young women (average age 20.5) and obtained blood samples to measure plasma ACTH concentrations immediately after venepuncture and again after 15 min of group activities designed to facilitate interpersonal attachment and stress-buffering. RESULTS: ACTH levels decreased in 70% of all participants throughout the group activities. A two-way repeated measures ANOVA highlighted a significant interaction between time and OC use, indicating differential changes in ACTH levels during social interaction between OC users and NC women. Further, the post-hoc analysis revealed that a period of stress-buffering group activities significantly decreased ACTH levels in NC women during menstrual and secretory phases, but not during the proliferative phase. In contrast, OC users did not display a decrease during group activities, regardless of the phase. CONCLUSION: This study underscores the influence of OC use on stress regulation, demonstrating that OCs not only modulate reproductive functions but also impact ACTH stress reactivity. Additionally, it emphasizes the importance of considering hormonal contraceptive use and menstrual cycle phases when assessing female stress responses.

Influence of sex hormones status and type of training on regional bone mineral density in exercising females.

The primary objective of this study was to examine the influence of hormonal ovarian profile and training characteristics on spine, pelvis, and total body bone mineral density (BMD) in a group of well-trained females. Forty-two eumenorrheic females, twenty-eight monophasic oral contraceptive (OC) users and thirteen postmenopausal females participated in this study. Body composition was measured by total body dual-energy X-ray absorptiometry (DXA) to determine BMD of the areas of interest. Endurance-trained premenopausal females showed lower spine BMD compared to resistance-trained premenopausal females (1.03 ± 0.1 vs. 1.09 ± 0.09 g/cm2; p = 0.025). Postmenopausal females reported lower BMD level in comparison to eumenorrheic females in pelvis (1.079 ± 0.082 vs 1.19 ± 0.115 g/cm2; p = 0.005), spine (0.969 ± 0.097 vs 1.069 ± 0.109 g/cm2; p = 0.012) and total (1.122 ± 0.08 vs 1.193 ± 0.077 g/cm2; p = 0.018) and OC users whose duration of OC use was less than 5 years (OC < 5) in pelvis (1.235 ± 0.068 g/cm2; p < 0.001) and spine (1.062 ± 0.069 g/cm2; p = 0.018). In addition, lower BMD values were found in OC users who had been using OC for more than 5 years (OC ≥ 5) than eumenorrheic females in pelvis (1.078 ± 0.086 g/cm2; p = 0.029) and spine (0.966 ± 0.08 g/cm2; p = 0.05). Likewise, OC ≥ 5 showed lower values than and OC < 5 in pelvis (p = 0.004) and spine (p = 0.047). We observed a lower spine BMD value in premenopausal endurance-trained females compared to premenopausal resistance-trained females. Moreover, this research observed that prolonged use of OCs may reduce bone mass acquisition in the spine and pelvis, even in well-trained females. Finally, postmenopausal showed lower BMD despite being exercising women.Trial registration: ClinicalTrials.gov identifier: NCT04458662.Highlights Ovarian hormonal profile should be considered when assessing BMD in female athletes.The duration of oral contraceptive use influences spine and pelvis regional BMD in exercising females.Postmenopausal women show lower BMD when compared to premenopausal females despite being exercising females.

Effect of oral contraceptive pills on the retinal microvascular structure: An optical coherence tomography angiography study.

BACKGROUND: To investigate the effect of oral contraceptive pills (OCPs) on foveal avascular zone (FAZ), peripapillary capillary plexus, and superficial and deep capillary plexus (SCP and DCP) measurements. METHODS: This cross-sectionally designed study included 32 healthy female participants using OCPs (3 mg drospirenone and 0.03 mg ethinylestradiol) for at least one year for contraception and 32 healthy controls that did not use any drugs. All subjects were evaluated using optical coherence tomography angiography (OCTA). Using OCTA, the measurements of SCP, DCP, radial peripapillary capillary (RPC) vessel density; FAZ area and perimeter; acircularity index (AI); and foveal density (FD) were undertaken. Each participant's measurements were taken while they were in the follicular phase of their menstrual cycles (day 3). RESULTS: Age and body mass index did not significantly differ between the groups (p = 0.56 and p = 0.15, respectively). The DCP vessel densities in all the regions were lower in the OCP group (p<0.05 for all). The vessel densities of SCP and RPC, FAZ area and perimeter, AI, and FD were similar between the two groups (p>0.05 for all). CONCLUSION: We determined that the DCP vessel density was reduced in women using this drug. OCPs can cause changes in retinal microvascular structures. Therefore, OCTA can be used in the follow-up of healthy women using OCP.

Do oral contraceptives modulate the effects of stress induction on one-session exposure efficacy and generalization in women?

RATIONALE: The administration of glucocorticoids (GC) as an adjunct to exposure represents a promising strategy to improve one-session exposure outcome in anxiety disorders. It remains to be determined whether similar effects can be induced with the use of acute stress. Furthermore, the possible modulation of exposure effects by hormonal factors (e.g., use of oral contraceptives (OCs)) was not explored so far. OBJECTIVES: We investigated whether acute stress prior to one-session exposure for spider fear affects its efficacy in women using oral contraceptives (OC) relative to free-cycling (FC) women. In addition, effects of stress on generalization of exposure therapy effects towards untreated stimuli were examined. METHODS: Women with fears of spiders and cockroaches were randomly assigned to a Stress (n = 24) or No-Stress (n = 24) condition prior to one-session exposure. Of these 48 participants, 19 women used OC (n = 9 in the Stress, and n = 10 in the No-Stress group). All FC women had a regular menstrual cycle and were tested only in the follicular phase of their menstrual cycle. Pre-exposure stress induction was realized with the socially evaluated cold-pressor test. Exposure-induced changes towards treated and untreated fear stimuli were tested with behavioral approach tests for spiders and cockroaches and subjective fear and self-report measures. RESULTS: Acute stress did not influence exposure-induced reduction in fear and avoidance of the treated stimuli (spiders). Similarly, stress had no effect on the generalization of exposure-therapy effects towards untreated stimuli (cockroaches). Exposure-induced reduction in subjective fear and self-report measures for treated stimuli was less evident in women using OC specifically after pre-exposure stress. Women using OC had higher levels of subjective fear and scored higher in self-report measures at post-treatment (24 h after exposure) and follow-up (4 weeks after exposure). CONCLUSIONS: OC intake may represent an important confounding factor in augmentation studies using stress or GC.

The Effects of Hormone Contraceptives and Menstruation on Object Memory and Spatial Ability in Young Women.

The aim of this study is to examine the relationship between hormone contraceptive use and menstruation on cognitive performance in young women. The object array task assessed object memory and a mental rotations test assessed spatial ability in women taking hormone contraceptives and naturally cycling women. Women taking hormone contraceptives were significantly better than naturally cycling women at identifying novel objects on an object array, but not on performance of a mental rotations task. There were also no significant differences in either task between naturally cycling women who were menstruating and those who were not menstruating during testing. The results of this study suggest that women taking hormone contraceptives outperformed naturally cycling women in recalling the identities of objects. The findings from this study help to further demonstrate the relationship between ovarian hormones and cognitive performance and add to the understanding of how hormone contraceptives affect cognition.

Oral contraceptive use and menstrual cycle influence acute cerebrovascular response to standing.

PURPOSE: To determine if the menstrual cycle and oral contraceptives (OC) influence responses to acute orthostatic stress and if these factors are clinically relevant to the diagnosis of initial orthostatic hypotension (iOH). METHODS: Young, healthy women were recruited, including OC users (n = 12) and non-users (NOC; n = 9). Women were tested during the low hormone (LH; placebo pills; days 2-5 natural cycle) and high hormone (HH; active dose; days 18-24 natural cycle) menstrual phases. Changes in mean arterial pressure, cardiac output, heart rate, the 30:15 heart rate ratio and cerebrovascular resistance indices within 30 s of standing were examined. RESULTS: There were no effects of OC or menstrual cycle on hemodynamic responses during standing (all p>0.05). In the LH phase, OC users had a greater fall in mean middle cerebral artery blood velocity (MCAV) compared to NOC (p<0.05). However, this was reversed in the HH phase, where OC users had a reduced fall in mean MCAV (p<0.05). Interestingly, 8 women (OC and NOC) had drops in systolic/diastolic blood pressure meeting the criteria for iOH, and 7 of those 8 women displayed this drop in a single phase of the menstrual cycle. CONCLUSION: Our results indicate that chronic versus acute OC use (i.e., long-term use observed via LH phase versus short-term use observed via HH phase) have opposing effects on cerebral blood velocity during standing. Further, our results highlight that multiple assessments across the cycle may be necessary to accurately diagnose iOH, as most women met the diagnostic criteria during a single menstrual phase.

Microvascular endothelial function following cessation of long-term oral contraceptive pill use: A case report.

NEW FINDINGS: What is the main observation in this case? The main observation of this case report is substantial improvement in cutaneous microvascular endothelial function after cessation of long-term use of a fourth-generation oral contraceptive pill. This improvement appears independent of relative changes in the contribution of nitric oxide. What insights does it reveal? Our findings suggest that cessation of long-term, fourth-generation oral contraceptive pill use improves endothelial function within 20 months of cessation. ABSTRACT: The purpose of this case report was to evaluate in vivo endothelial function and nitric oxide (NO)-dependent vasodilatation before and after the cessation of long-term (11-12 years) fourth-generation oral contraceptive pill (OCP) use in one young, healthy and premenopausal woman. This retrospective analysis includes data from six experimental visits: three visits during months 133-144 of fourth-generation OCP use and three visits 19-22 months after OCP cessation. Endothelium-dependent and NO-dependent vasodilatation were assessed in the cutaneous microvasculature using laser-Doppler flowmetry, a rapid local heating protocol (39°C, 0.1°C/s) and pharmacological perfusion through intradermal microdialysis fibres. The participant had consistent medical history and lifestyle behaviours throughout both hormonal exposures. Data are presented as the mean (SD). Endothelium-dependent vasodilatation was 42 (10)% of site-specific maximal cutaneous vascular conductance (CVCmax ) during OCP use and 63 (10)%CVCmax after OCP cessation (49% increase). Nitric oxide-dependent vasodilatation was 70 (5)% contribution of NO during OCP use and 60 (15)%NO after OCP cessation (15% reduction). Baseline blood flow was greater after OCP cessation, but maximal blood flow was reduced. Data from this case report support a substantial increase in cutaneous microvascular endothelial function assessed via local heating after cessation of long-term use of a fourth-generation OCP, which does not appear to be attributable to increased NO bioavailability. Overall, these data suggest an improvement in endothelial and microvascular function after the cessation of long-term use of a fourth-generation OCP.

Effects of oral contraceptives on spatial cognition depend on pharmacological properties and phase of the contraceptive cycle.

The central nervous system effects of oral contraceptives (OCs) are not well-documented. In a set of 3 studies, we investigated a specific cognitive function, mental rotation, in healthy women currently using OCs for contraceptive purposes (n = 201) and in medication-free controls not using OCs (n = 44). Mental rotation was measured using a well-standardized and extensively validated psychometric test, the Vandenberg Mental Rotations Test (MRT). In an initial study (Study 1), current OC users (n = 63) were tested during the active or inactive phases of the contraceptive cycle in a parallel-groups design. Studies 2 and 3 were based on an archival dataset (n = 201 current OC users) that consisted of data on the MRT collected in real-time over a 30-year period and compiled for purposes of the present work. The OCs were combined formulations containing ethinyl estradiol (10-35 ug/day) plus a synthetic progestin. All 4 families of synthetic progestins historically used in OCs were represented in the dataset. Cognitive performance was evaluated during either active OC use ('active phase') or during the washout week of the contraceptive cycle ('inactive phase') when OC steroids are not used. The results showed a significant phase-of-cycle (POC) effect. Accuracy on the MRT was mildly diminished during the active phase of OC use, while scores on verbal fluency and speeded motor tasks were modestly improved. The POC effect was most evident in women using OCs that contained first- or second-generation progestins (the estrane family of progestins or OCs containing levonorgestrel), but not in women using OCs containing recently developed progestins and lower doses of ethinyl estradiol. Using independently established ratings of the estrogenic, androgenic, and progestogenic intensities of the different OC formulations, each brand of OC was classified according to its distinct endocrine profile. Multiple regression revealed that the effects of OC use on the MRT could be predicted based on the estrogenic strength of the contraceptives used. Estrogenic potency, not androgenic or anti-androgenic effects of the OC pill, may underlie the effects of OC usage on spatial cognition.

Continuous 17α-ethinylestradiol exposure impairs the sperm quality of marine medaka (Oryzias melastigma).

17α-ethinylestradiol (EE2) is an anthropogenic estrogen that is widely used for hormone therapy and oral contraceptives. It was reported that EE2 exposure induced reproductive impairments through processes affecting reproduction behavior and inducing ovotestis. However, the effects of continuous EE2 exposure on the reproductive performance remain largely unknown. In this study, adult marine medaka fish (Oryzias melastigma) were exposed to EE2 (85 ng/L) for one (F0) and two (F1) generations. Our results indicate that continuous EE2 exposure reduced fecundity and sperm motility. The testicular transcriptome, followed by bioinformatic analysis revealed the dysregulation of pathways related to steroidogenesis, sperm motility, and reproductive system development. Collectively, our findings indicate that continuous EE2 exposure directly affected sperm quality via the alteration of steroidogenesis and dysregulation of reproductive system development. The identified key factors including DNM1, PINK1, PDE7B, and SLC12A7 can serve as biomarkers to assess EE2-reduced sperm motility.

Imaging the human brain on oral contraceptives: A review of structural imaging methods and implications for future research goals.

Worldwide over 150 million women use oral contraceptives (OCs), which are the most prescribed form of contraception in both the United States and in European countries. Sex hormones, such as estradiol and progesterone, are important endogenous hormones known for shaping the brain across the life span. Synthetic hormones, which are present in OCs, interfere with the natural hormonal balance by reducing the endogenous hormone levels. Little is known how this affects the brain, especially during the most vulnerable times of brain maturation. Here, we review studies that investigate differences in brain gray and white matter in women using OCs in comparison to naturally cycling women. We focus on two neuroimaging methods used to quantify structural gray and white matter changes, namely structural MRI and diffusion MRI. Finally, we discuss the potential of these imaging techniques to advance knowledge about the effects of OCs on the brain and wellbeing in women.

The effect of sex, menstrual cycle phase and oral contraceptive use on intestinal permeability and ex-vivo monocyte TNFα release following treatment with lipopolysaccharide and hyperthermia.

PURPOSE: Investigate the impact of sex, menstrual cycle phase and oral contraceptive use on intestinal permeability and ex-vivo tumour necrosis factor alpha (TNFα) release following treatment with lipopolysaccharide (LPS) and hyperthermia. METHODS: Twenty-seven participants (9 men, 9 eumenorrheic women (MC) and 9 women taking an oral contraceptive pill (OC)) completed three trials. Men were tested on 3 occasions over 6 weeks; MC during early-follicular, ovulation, and mid-luteal phases; OC during the pill and pill-free phase. Intestinal permeability was assessed following a 4-hour dual sugar absorption test (lactulose: rhamnose). Venous blood was collected each trial and stimulated with 100 µg·mL-1 LPS before incubation at 37 °C and 40 °C and analysed for TNFα via ELISA. RESULTS: L:R ratio was higher in OC than MC (+0.003, p = 0.061) and men (+0.005, p = 0.007). Men had higher TNFα responses than both MC (+53 %, p = 0.004) and OC (+61 %, p = 0.003). TNFα release was greater at 40 °C than 37 °C (+23 %, p < 0.001). CONCLUSIONS: Men present with lower resting intestinal barrier permeability relative to women regardless of OC use and displayed greater monocyte TNFα release following whole blood treatment with LPS and hyperthermia. Oral contraceptive users had highest intestinal permeability however, neither permeability or TNFα release were impacted by the pill cycle. Although no statistical effect was seen in the menstrual cycle, intestinal permeability and TNFα release were more variable across the phases.

Oral contraceptives and stroke: Foes or friends.

Incidents of strokes are increased in young women relative to young men, suggesting that oral contraceptive (OC) use is one of the causes of stroke among young women. Long-term exposures to the varying combinations of estrogen and progestogen found in OCs affect blood clotting, lipid and lipoprotein metabolism, endothelial function, and de novo synthesis of neurosteroids, especially brain-derived 17ß-estradiol. The latter is essential for neuroprotection, memory, sexual differentiation, synaptic transmission, and behavior. Deleterious effects of OCs may be exacerbated due to comorbidities like polycystic ovary syndrome, sickle cell anemia, COVID-19, exposures to endocrine disrupting chemicals, and conventional or electronic cigarette smoking. The goal of the current review is to revisit the available literature regarding the impact of OC use on stroke, to explain possible underlying mechanisms, and to identify gaps in our understanding to promote future research to reduce and cure stroke in OC users.

Menstrual cycle and oral contraceptives influence cerebrovascular dynamics during hypercapnia.

Women experience fluctuating orthostatic intolerance during the menstrual cycle, suggesting sex hormones may influence cerebral blood flow. Young (aged 18-30) healthy women, either taking oral contraceptives (OC; n = 14) or not taking OC (NOC; n = 12), were administered hypercapnic gas (5%) for 5 min in the low hormone (LH; placebo pill) and high hormone (HH; active pill) menstrual phases. Hemodynamic and cerebrovascular variables were continuously measured. Cerebral blood velocity changes were monitored using transcranial doppler ultrasound of the middle cerebral artery to determine cerebrovascular reactivity. Cerebral autoregulation was assessed using steady-state analysis (static cerebral autoregulation) and transfer function analysis (dynamic cerebral autoregulation; dCA). In response to hypercapnia, menstrual phase did not influence static cardiovascular or cerebrovascular responses (all p > 0.07); however, OC users had a greater increase of mean middle cerebral artery blood velocity compared to NOC (NOC-LH 12 ± 6 cm/s vs. NOC-HH 16 ± 9 cm/s; OC-LH 18 ± 5 cm/s vs. OC-HH 17 ± 11 cm/s; p = 0.048). In all women, hypercapnia improved high frequency (HF) and very low frequency (VLF) cerebral autoregulation (decreased nGain; p = 0.002 and <0.001, respectively), whereas low frequency (LF) Phase decreased in NOC-HH (p = 0.001) and OC-LH (p = 0.004). Therefore, endogenous sex hormones reduce LF dCA during hypercapnia in the HH menstrual phase. In contrast, pharmaceutical sex hormones (OC use) have no acute influence (HH menstrual phase) yet elicit a chronic attenuation of LF dCA (LH menstrual phase) during hypercapnia.

Blood oxidative stress biomarkers in women: influence of oral contraception, exercise, and N-acetylcysteine.

PURPOSE: To compare physiological responses to submaximal cycling and sprint cycling performance in women using oral contraceptives (WomenOC) and naturally cycling women (WomenNC) and to determine whether N-acetylcysteine (NAC) supplementation mediates these responses. METHODS: Twenty recreationally trained women completed five exercise trials (i.e., an incremental cycling test, a familiarisation trial, a baseline performance trial and two double-blind crossover intervention trials). During the intervention trials participants supplemented with NAC or a placebo 1 h before exercise. Cardiopulmonary parameters and blood biochemistry were assessed during 40 min of fixed-intensity cycling at 105% of gas-exchange threshold and after 1-km cycling time-trial. RESULTS: WomenOC had higher ventilation (ß [95% CI] = 0.07 L·min-1 [0.01, 0.14]), malondialdehydes (ß = 12.00 mmol·L-1 [6.82, 17.17]) and C-reactive protein (1.53 mg·L-1 [0.76, 2.30]), whereas glutathione peroxidase was lower (ß =  22.62 mU·mL-1 [- 41.32, - 3.91]) compared to WomenNC during fixed-intensity cycling. Plasma thiols were higher at all timepoints after NAC ingestion compared to placebo, irrespective of group (all p < 0.001; d = 1.45 to 2.34). For WomenNC but not WomenOC, the exercise-induced increase in malondialdehyde observed in the placebo trial was blunted after NAC ingestion, with lower values at 40 min (p = 0.018; d = 0.73). NAC did not affect cycling time-trial performance. CONCLUSIONS: Blood biomarkers relating to oxidative stress and inflammation are elevated in WomenOC during exercise. There may be an increased strain on the endogenous antioxidant system during exercise, since NAC supplementation in WomenOC did not dampen the exercise-induced increase in malondialdehyde. Future investigations should explore the impact of elevated oxidative stress on exercise adaptations or recovery from exercise in WomenOC.