Active Pill Research Articles

The Effect of the Oral Contraceptive Pill on Acute Glycaemic Response to an Oral Glucose Bolus in Healthy Young Women: A Randomised Crossover Study.

Background/Objective: The oral contraceptive pill (OCP) is widely used by women worldwide, yet the influence of the OCP on carbohydrate metabolism remains under-investigated, with existing studies being few and largely cross-sectional. The study objective was to assess, for the first time, the effect of the combined OCP on postprandial glycaemic response to an oral glucose bolus, using a randomised crossover design. Methods: The effect of a combined monophasic OCP phase on glucose homeostasis and metabolic profile was investigated in 21 healthy young women, who were regular users of either androgenic or anti-androgenic OCP formulations. Plasma glycaemic markers (glucose, insulin and C-peptide) were assessed prior to a 60 g glucose drink (fasting) and for a further 4 h postprandially; once during the "active" (hormone-containing) pill phase and once during the "inactive" (hormone-free) pill phase of the OCP usage cycle. Results: Despite no change in fasting values, in androgenic pill users, postprandial glucose and insulin responses to an oral glucose bolus were ~100% and ~50% greater, respectively, during the active versus inactive phase. In contrast, in anti-androgenic pill users there was no significant change in response between the two OCP usage cycle phases. Conclusions: These findings highlight an acute, but potentially detrimental, influence of the combined OCP on glucose homeostasis, particularly in users of formulations containing androgenic progestogens. Given the high global prevalence of OCP use and increasingly common prolonged active pill regimens, which may continue for months, years or even decades, potential cumulative effects of such changes on metabolic risk demand further investigation.

Influence of menstrual cycle and oral contraceptive phases on strength performance, neuromuscular fatigue, and perceived exertion.

The primary aim of the study was to assess differences in strength performance, neuromuscular fatigue, and perceived exertion across phases of the menstrual cycle [MC; early follicular (eFP), late follicular (lFP), and mid-luteal phase (mLP)] and oral contraceptives [OCs; active pill phase (aPP) and nonactive pill phase (nPP)]. The secondary aim was to analyze the influence of fluctuating serum 17β-estradiol and progesterone concentrations on these parameters in naturally menstruating women. Thirty-four women (21 with a natural MC and 13 using OCs) completed three or two experimental sessions, respectively. Mean propulsive velocity (MPVmean) and total number of repetitions (REPtotal) were assessed during a power [3 × 8 at 60% 1RM (one-repetition maximum)] and hypertrophy squat loading (3 sets to failure at 70% 1RM), respectively. Changes in bench press and squat MPV at 60% 1RM in response to the loadings were used as surrogates for nonlocal and local fatigue, respectively. Total blood lactate accumulation (BLAA) and markers of perceived exertion were assessed in each session. No significant differences between any of the MC or OC phases were observed for MPVmean, REPtotal, nonlocal and local fatigue, and markers of perceived exertion (all P > 0.050). A higher intraindividual 17β-estradiol concentration was significantly associated with a lower MPVmean (P = 0.019). BLAA was significantly higher in the lFP than in the mLP (P = 0.019) and negatively associated with the intraindividual progesterone concentration (P = 0.005). Although 17β-estradiol may negatively influence the MPV, it appears that fluctuations of both sex hormones across the MC and OC phases are not prominent enough to induce significant or practically relevant changes in the assessed parameters.NEW & NOTEWORTHY Although a high intraindividual 17β-estradiol concentration was associated with a lower movement velocity, markers of strength performance and surrogates for nonlocal and local fatigue remained unaffected by MC and OC phases. Blood lactate accumulation was significantly reduced in the mLP. Furthermore, our findings suggest that the impact of the MC phases varies greatly among individuals. Individuals with high fluctuations in sex hormone concentrations may experience relevant changes in the assessed parameters.

Emotion and birth control: Emotion regulation ERPs differ based on menstrual cycle phase and hormonal contraceptive use

While hormonal contraceptives (HCs) like oral contraceptive pills (OCs) and intrauterine devices (IUDs) can reportedly influence mood, the evidence is mixed, and the mechanisms remain unclear. Emotion reactivity and regulation processes may be hormone-sensitive and underlie these mood changes. This study sought to investigate the role of the menstrual cycle and HC use in emotion regulation using ERP measures during an emotion regulation paradigm. Participants with a natural cycle (NC) were measured in the mid-follicular and mid-luteal phase (within-subject design, n = 26), and compared with OC (n = 36) and IUD (n = 25) users. The centroparietal late positive potential (LPP) reflected negative emotion reactivity and its modulation by cognitive reappraisal served as a marker for emotion regulation processing. NC participants had a lower LPP amplitude in the mid-luteal compared to the mid-follicular phase. Reactivity to negative emotional stimuli decreased over time in the mid-luteal phase, whereas the HC groups showed sustained LPP activation. Reappraisal led only to significant LPP changes in the mid-follicular phase, and not in the mid-luteal phase or HC groups. Our results showed a specific left frontal activity (FR-LPP) in the contrast that reflected emotion regulation processing. This activity was highest in the mid-follicular phase, and was significantly different from the OC users but not from the IUD group. Higher self-reported PMS symptoms were associated with stronger effects on the reduced mid-luteal LPP activity and with lower FR-LPP amplitude in the mid-follicular phase. No effect of OC phase (active pill use versus pill pause) was found. These findings add insights into the neurophysiological underpinnings of hormone-related mood changes and demonstrate the importance of considering hormonal status and PMS symptoms in emotion research.

Influence of endogenous and exogenous hormones on the cardiovascular response to lower extremity exercise and group III/IV activation in young females.

Oral contraceptive (OC) use can increase resting blood pressure (BP) in females as well as contribute to greater activation of group III/IV afferents during upper body exercise. It is unknown, however, whether an exaggerated BP response occurs during lower limb exercise in OC users. We sought to elucidate the group III/IV afferent activity-mediated BP and heart rate responses while performing lower extremity tasks during early and late follicular phases in young, healthy females. Females not taking OCs (NOC: n = 8; age: 25 ± 4 yr) and those taking OCs (OC: n = 10; age: 23 ± 2 yr) completed a continuous knee extension/flexion passive stretch (mechanoreflex) and cycling exercise with subsystolic cuff occlusion (exercise pressor reflex), which was followed by a 2-min postexercise circulatory occlusion (PECO) (metaboreflex). Data collection occurred on two occasions: once during the early follicular phase (days 1-4) and once during the late follicular phase (days 10-14) of their menstrual cycle (NOC) or during the placebo and active pill phases (OC). Resting mean arterial BP and heart rate were not different between phases in NOC and OC participants (P > 0.05). Hemodynamic responses to metaboreflex, mechanoreflex, and collective exercise pressor reflex activation were not different between phases in both groups (P > 0.05). In conclusion, although OCs are known to increase BP at rest, our findings indicate that neither endogenous nor exogenous (OC) sex hormones modulate BP during large, lower limb muscle exercise with or without group III/IV afferent activation in young, healthy females.NEW & NOTEWORTHY Sex differences in the cardiovascular response to exercise have been demonstrated and may be dependent on sex hormone levels. Furthermore, oral contraceptives (OCs) have been shown to exaggerate the blood pressure response to upper extremity exercise. The results of this study indicate that neither endogenous nor exogenous (OC) sex hormones modulate BP during lower extremity dynamic exercise or with group III/IV afferent activation in young, healthy females.

The hormonal profile in women using combined monophasic oral contraceptive pills varies across the pill cycle: a temporal analysis of serum endogenous and exogenous hormones using liquid chromatography with tandem mass spectroscopy.

Oral contraceptive pills, of all types, are used by approximately 151 million women worldwide; however, a clear understanding of the concentrations of endogenous and exogenous hormones across a 28-day combination monophasic oral contraceptive pill pack is not well described. In our study of 14 female participants taking various combination monophasic oral contraceptive pills, we found significant fluctuations in endogenous and exogenous hormone levels throughout the pill cycle. Our analysis revealed significantly greater levels of ethinyl estradiol on the 20th and 21st days of active pill ingestion, compared with days 1-2 (active) and days 27-28 (inactive pill ingestion). Conversely, estradiol concentrations decreased during active pill consumption, while progestin and progesterone levels remained stable. During the 7 days of inactive pill ingestion, estradiol levels rose sharply and were significantly higher at days 27-28 compared with the mid and late active phase time points, while ethinyl estradiol declined and progestin did not change. These findings challenge the previous assumption that endogenous and exogenous hormones are stable throughout the 28-day pill cycle.NEW & NOTEWORTHY The results from this study have wide-ranging implications for research and treatment in women's health including considerations in research design and interpretation for studies including women taking oral contraceptives, the potential for more precise and personalized methods of dosing to reduce unwanted side effects and adverse events, and the potential treatment of a variety of disorders ranging from musculoskeletal to neurological with exogenous hormones.

Effects of In-Exercise Carbohydrate Supplementation on Prolonged High-Intensity Exercise Performance in Oral Contraceptive Users.

To examine the impact of oral contraceptive (OC) phases on performance, physiological, and subjective responses to prolonged, intensive exercise when carbohydrate (CHO) stores are reduced. Ten well-trained female cyclists using monophasic OC completed 4 identical trials (>150min) under conditions of in-trial 60-g·h-1 CHO supplementation (CHO+) or placebo (CHO-) during the sugar- (SUG) and active-pill (ACT) phases of their OC cycle. Each trial comprised two 400-kcal time trials (TT) separated by 1hour of submaximal cycling at first ventilatory threshold. Change in completion time from TT1 to TT2 was minimized in CHO+ compared with CHO- (4.06 [2.55] vs 6.08 [5.33]min; P = .019, effect size = -0.36). An interaction effect of OC and CHO was observed for time to complete TT (P = .006), mean TT power (P = .002), mean TT heart rate (P = .002), and posttrial emotional balance (P = .020) and negative emotional state (P = .033). In ACT, mean TT power and heart rate were higher in CHO+ when compared with CHO-, resulting in faster TTs in CHO+ and improved posttrial emotional well-being. When CHO was not supplemented, TT power and heart rate were higher in SUG when compared with ACT, resulting in faster TTs in SUG and improved posttrial emotional balance. CHO depletion during ACT negatively influenced TT performance and emotional well-being when compared with SUG. Irrespective of OC pill phase, CHO supplementation should be prioritized to sustain performance and improve postexercise recovery-stress balance.

Preliminary evidence of increased alcohol use associated with ethinyl estradiol levels in women using oral contraceptives

Alcohol use is highly prevalent in young adult women and rates of alcohol use disorder are rising rapidly in this population. Further, emerging evidence suggests that circulating levels of ovarian hormones influence alcohol consumption, with increased consumption associated with higher estradiol and lower progesterone levels. However, less is known about the influence of synthetic hormones (contained in oral contraceptive (OC) pills) on alcohol use. The current study examined the influence of OC pill phase, ethinyl estradiol (EE) levels, and progestin levels on self-reported alcohol consumption in healthy female drinkers. Young adult female drinkers using OCs (N = 21) reported alcohol use across one OC pill pack using the Timeline Followback and provided blood samples during both pill phases to measure synthetic hormone levels. We compared alcohol use between OC pill phases (active vs. inactive) using linear mixed effects models for repeated measures and examined correlations between alcohol use and EE and progestin levels. Results showed that women with higher EE levels reported increased alcohol consumption (r = 0.56, p = 0.01) and binge drinking (r = 0.45, p = 0.04) in the active pill phase. Progestin levels and pill phase were not significantly associated with alcohol consumption. These findings provide preliminary data suggesting increased levels of EE from OC pills are associated with excessive alcohol consumption in women. Further research is needed to determine if EE plays a causal role in increased alcohol consumption. This line of research could inform female-specific AUD prevention and treatment strategies among the large subpopulation of women using hormonal contraceptives.

Mental Health Symptoms in Oral Contraceptive Users During Short-Term Hormone Withdrawal

Hormonal 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. To 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. This 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. COC 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. Negative 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. A 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. In 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.

Endogenous estradiol contributes to vascular endothelial dysfunction in premenopausal women with type 1 diabetes

BackgroundEndogenous estrogen is cardio-protective in healthy premenopausal women. Despite this favorable action of estrogen, animal models depict a detrimental effect of estradiol on vascular function in the presence of diabetes. The present study sought to determine the role of endogenous estradiol on endothelial function in women with type 1 diabetes.Method32 women with type 1 diabetes (HbA1c = 8.6 ± 1.7%) and 25 apparently healthy women (HbA1c = 5.2 ± 0.3%) participated. Flow-mediated dilation (FMD), a bioassay of nitric-oxide bioavailability and endothelial function was performed during menses (M) and the late follicular (LF) phase of the menstrual cycle to represent low and high concentrations of estrogen, respectively. In addition, a venous blood sample was collected at each visit to determine circulating concentrations of estradiol, thiobarbituric acid reactive substances (TBARS), and nitrate/nitrite (NOx), biomarkers of oxidative stress and nitric oxide, respectively. Data were collected in (1) 9 additional women with type 1 diabetes using oral hormonal birth control (HBC) (HbA1c = 8.3 ± 2.1%) during the placebo pill week and second active pill week, and (2) a subgroup of 9 demographically matched women with type 1 diabetes not using HBC (HbA1c = 8.9 ± 2.1%).ResultsOverall, estradiol was significantly increased during the LF phase compared to M in both type 1 diabetes (Δestradiol = 75 ± 86 pg/mL) and controls (Δestradiol = 71 ± 76 pg/mL); however, an increase in TBARS was only observed in patients with type 1 diabetes (ΔTBARS = 3 ± 13 µM) compared to controls (ΔTBARS = 0 ± 4 µM). FMD was similar (p = 0.406) between groups at M. In addition, FMD increased significantly from M to the LF phase in controls (p = 0.024), whereas a decrease was observed in type 1 diabetes. FMD was greater (p = 0.015) in patients using HBC compared to those not on HBC, independent of menstrual cycle phase.ConclusionEndogenous estradiol increases oxidative stress and contributes to endothelial dysfunction in women with diabetes. Additionally, HBC use appears to be beneficial to endothelial function in type 1 diabetes.

Impact of aerobic fitness status, menstrual cycle phase, and oral contraceptive use on exercise substrate oxidation and metabolic flexibility in females.

The influence of menstrual cycle phase and fitness status on metabolism during high-intensity interval exercise (HIIE) was assessed. Twenty-five females (24.4 (3.6) years) were categorized by normal menstrual cycle (n=14) vs. oral contraceptive (OC) use (n=11) and by aerobic fitness, high-fitness females (HFF; n=13) vs. low-fitness females (LFF; n=12). HIIE was four sets of four repetitions with a 3min rest between intervals on a cycle ergometer at a power output halfway between the ventilatory threshold and V̇O2peak and performed during follicular (FOL: days 2-7 or inactive pills) and luteal phases (LUT: day ∼21 or 3rd week of active pills). Substrate oxidation was assessed via indirect calorimetry, blood lactate via finger stick, and recovery of skeletal muscle oxidative metabolism (mV̇O2) via continuous-wave near-infrared spectroscopy. HFF oxidized more fat (g·kg-1) during the full session (FOL: p=0.050, LUT: p=0.001), high intervals (FOL: p=0.048, LUT: p=0.001), low intervals (FOL: p=0.032, LUT: p=0.024), and LUT recovery (p=0.033). Carbohydrate oxidation area under the curve was greater in HFF during FOL (FOL: p=0.049, LUT: p=0.124). Blood lactate was lower in LFF in FOL (p≤0.05) but not in LUT. Metabolic flexibility (Δ fat oxidation g·kg-1·min-1) was greater in HFF than LFF during intervals 2-3 in FOL and 1-4 in LUT (p≤0.05). Fitness status more positively influences exercise metabolic flexibility during HIIE than cycle phase or OC use.

Fatigue Resistance Is Altered during the High-Hormone Phase of Eumenorrheic Females but not Oral Contraceptive Users.

To examine the effect of ovarian hormones and their synthetic equivalents on substrate utilisation and fatigue resistance during a race-specific cycling protocol. 17 well-trained female cyclists (9 eumenorrheic females, 8 oral contraceptive users), completed two experimental trials, in a randomised order, in their low (follicular/sugar pill) and high-hormone (luteal/active pill) phases. Each 91-min trial consisted of a 45-min moderate-intensity component (SMC) followed by 6-min of high-intensity (HIT) and then a fatigue resistance test (FRT): 6x1-min all-out efforts with 1-min active recovery. Meals, comprising carbohydrate (CHO) intake of 8 g.kg-1 body mass, were standardised 24-h pre-trial. An electrolyte-only solution was provided ad-libitum during each trial. In eumenorrheic females, a large reduction in average power during FRT was observed in the luteal phase (277 ± 31 vs. 287 ± 33 W; P = 0.032). Greater CHOox (~ 4 %, P = 0.020) during SMC and ventilatory inefficiencies during SMC and HIT (~ 7 %, P < 0.001) were also observed in the luteal phase. In OC users, despite some phasal changes in cardiorespiratory and metabolic data in SMC (~6% higher blood glucose and ~ 2% higher minute ventilation in active pill phase), none of the performance parameters in the FRT were different. Fatigue resistance was compromised only in high-hormone phase of the menstrual cycle, with eumenorrheic females likely susceptible due to increased CHO utilisation during SMC. Hormone-induced ventilatory inefficiencies may also have increased metabolic demand. These findings emphasise the need to maintain CHO availability for power production, particularly in high-hormone phases.

The anaemia treatment journey of CKD patients: from epoetins to hypoxia-inducible factor-prolyl hydroxylase inhibitors.

The discovery and development of erythropoiesis-stimulating agents was a journey lasting more than a century, leading to the cloning and approval of recombinant human erythropoietin (rHuEpo). This was an impressive clinical advance, providing the possibility of correcting the symptoms associated with anaemia in chronic kidney disease. Associated iron use was needed to produce new haemoglobin-containing blood red cells. Partial anaemia correction became the standard of care since trials aiming for near-normal haemoglobin levels showed a higher risk of adverse cardiovascular events. Hoping to reduce the cardiovascular risks, a new category of drugs was developed and tested. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are small molecules than can be formulated into orally active pills. They simulate reduced tissue oxygen pressure, thus stimulating the production of endogenous erythropoietin (Epo) by the kidneys and liver. Clinical trials with these compounds demonstrated that HIF-PHIs are at least as effective as rHuEpo in treating or correcting anaemia in non-dialysis and dialysis patients. Trials with HIF-PHIs did not demonstrate superiority in safety outcomes and in some trials, outcomes were worse. There was also a focus on oral delivery, a possible beneficial iron-sparing effect and the ability to overcome Epo resistance in inflamed patients. A negative effect is possible iron depletion, which may explain adverse outcomes.

Does chronic oral contraceptive use detrimentally affect C-reactive protein or iron status for endurance-trained women?

Chronic use of the oral contraceptive pill (OCP) is reported to increase C-reactive protein (CRP) levels and increase the risk of cardiovascular disease in premenopausal females. A secondary analysis of data from two research studies in eumenorrheic (n = 8) and OCP (n = 8) female athletes. Basal CRP and iron parameters were included in the analysis. Sample collection occurred following a standardized exercise and nutritional control for 24 h. Eumenorrheic females were tested in the early-follicular and mid-luteal phases, and the OCP users were tested in quasi-follicular and quasi-luteal phases (both active pill periods). A main effect for group (p < 0.01) indicated that average CRP concentration was higher in OCP users compared with eumenorrheic females, regardless of the day of measurement within the cycle. Results demonstrate a degree of iron parameters moderation throughout the menstrual cycle that is influenced by basal CRP levels; however, no linear relationship with CRP, serum iron, and ferritin was observed. Basal CRP values were consistently higher in the OCP group despite participants being in a rested state. These results may indicate a potential risk of cardiovascular disease in prolonged users of the OCP when compared to eumenorrheic female athletes.

Changes in Visual Long-Term Potentiation Show Preserved Cyclicity in Human Females Taking Combined Oral Contraceptives

Introduction: The combined oral contraceptive (COC) pill is often employed to address physical and neurological symptoms in menstrual cycle-related disorders by suppressing shifts in endogenous gonadal hormone fluctuations. Symptom persistence, especially in the lead up to the hormone-free interval (HFI), suggests an underlying neurobiological mechanism of preserved cycling. Our study utilised a non-invasive method of visually inducing long-term potentiation (LTP) to index changes in neural plasticity in the absence of hormonal fluctuations. Methods: Visually induced LTP was recorded using electroencephalography in 24 healthy female COC users across three sessions: days 3 and 21 during active hormone pills, and day 24 during the HFI. The Daily Record of the Severity of Problems (DRSP) questionnaire tracked premenstrual symptoms. Dynamic causal modelling (DCM) was used to elucidate the neural connectivity and receptor activity changes associated with LTP across different days of COC. Results: Visually induced LTP was greater on day 21 than day 3 (p = 0.011) and was localised to the P2 visually evoked potential. There was no effect of the HFI (day 24) on LTP. DCM of differences between days 3 and 21 showed changes to inhibitory interneuronal gating of LTP in cortical layer VI. The DRSP only showed a significant increase in symptoms in the HFI, meaning the LTP result appeared more sensitive to cyclicity. Conclusions: This study provides objective evidence of preserved cyclicity in COC users through enhanced LTP on day 21 compared to day 3 of a 28-day COC regimen, indicating that relatively higher excitation in the brain despite peripheral gonadal suppression may underlie and exacerbate menstrual cycle-related disorders.

377 Randomized Placebo-controlled Trial to Test the Efficacy of genetically informed biomarker Nicotine Metabolite Ratio (NMR), and transdermal nicotine replacement therapy (NRT) versus varenicline

OBJECTIVES/GOALS: The overall aim of the proposed study is to evaluate the effectiveness and clinical utility of the NMR as a biomarker of response to placebo, transdermal nicotine, and varenicline to be utilized within the clinical practice as a point-of-care predictor to tailor an individual’s smoking cessation treatment. METHODS/STUDY POPULATION: A 12-week phase II, stratified multicenter, randomized, placebo-controlled trial of 3 treatment groups to measure treatment-seeking smokers (n-900:150 slow metabolizers; 150 normal metabolizers), randomized to 12-weeks of nicotine patch (active patch + placebo pill), varenicline (active pill + placebo patch), or placebo (placebo pill + patch). At the end of treatment, patients will be followed for 12 months. Study Population: Adult smokers 18–65 years old reported smoking≥10 cigarettes/day for≥6 months (verified by carbon monoxide (CO) &gt;10 ppm). Drug and route of administration: RESULTS/ANTICIPATED RESULTS: The study would conclude the effectiveness of the interventions well defined. DISCUSSION/SIGNIFICANCE: The report will provide robust evidence to support the effectiveness of NRT intervention on smoking cessation.

Nocturnal Heart Rate Variability in Women Discordant for Hormonal Contraceptive Use.

The aim of this study was to investigate within-cycle differences in nocturnal heart rate (HR) and heart rate variability (HRV) in naturally menstruating women (NM) and women using combined hormonal contraceptives (CU) or progestin-only hormonal contraceptives (PU). Physically active participants were recruited into three groups: NM ( n = 19), CU ( n = 11), and PU ( n = 12). Participants' HR and HRV (with Bodyguard 2 HRV monitor) and blood hormones were monitored during one menstrual cycle (MC) (NM group) or for 4 wk (CU and PU groups). Estradiol, progesterone, and luteinizing hormone were analyzed from fasting blood samples collected four times in the NM (M1 = bleeding, M2 = follicular phase, M3 = ovulation, and M4 = luteal phase) and PU groups (M1 = lowest E 2 , M2 = M1 + 7 d, M3 = M1 + 14 d, and M4 = M1 + 21 d) and twice in the CU group (active and inactive pill phases). After every blood sample, nightly HR and HRV were recorded and examined as an average from two nights. Hormonal concentrations differed ( P < 0.05) between MC phases in the NM and PU groups, but not ( P ≥ 0.116) between the active and the inactive phases in the CU group. In the NM and PU groups, some of the HRV values were higher, whereas in the NM group, HR was lower during M2 compared with M3 ( P < 0.049) and M4 ( P < 0.035). In the CU group, HRV values ( P = 0.014-0.038) were higher, and HR was lower ( P = 0.038) in the inactive phase compared with the first week of the active phase. The MC and the hormonal cycle phases influence autonomic nervous system balance, which is reflected in measurements of nocturnal HR and HRV. This should be considered when monitoring recovery in physically active individuals.

P056Oral contraceptive adherence and pregnancy rates in estetrol/drospirenone pooled phase 3 trials

<h3>Objectives</h3> To assess the relationship of adherence and pregnancy in participants using an estetrol and drospirenone combined oral contraceptive. <h3>Methods</h3> We pooled data from two parallel, multicenter, open-label, phase 3 trials (US/Canada and Europe/Russia) that enrolled healthy participants aged 16–50 to receive estetrol 15 mg/drospirenone 3 mg in a 24/4 regimen for up to 13 cycles. We limited this efficacy analysis to participants aged 16–35 at screening. Participants reported adherence using paper diaries. We assessed the relationship between number of missed pills and pregnancies in at-risk cycles (≥1 confirmed intercourse and no other contraceptive use) and when pregnancies occurred during product use with test for trend and chi-square analyses as appropriate. <h3>Results</h3> Among 3,027 participants in this analysis, 31 on-treatment pregnancies occurred during 26,455 at-risk cycles of use for an overall Pearl Index of 1.52 (95% CI, 1.04–2.16). Pregnancies occurred in 0.09%, 0.25%, 0.83%, and 1.6% of cycles in which participants reported missing 0 (n=25,613 cycles), 1 (n=405 cycles), 2 (n=121 cycles) and >2 (n=314 cycles) active pills, respectively (p<0.0001). Pregnancy rates ranged from 0-0.21% per cycle with no significant trend by cycle (p=0.45). About half (48.4%) of all pregnancies occurred in the first four cycles, with pregnancies occurring in 0.17% of cycles vs. 0.08% during cycles 5–8 and 0.10% in cycles 9–13 (p=0.07). <h3>Conclusions</h3> Pregnancy occurs more frequently when combined oral contraceptive users report missing pills and exceeds 1% only when >2 pills are missed. A 0.09% pregnancy risk among users reporting no missed pills likely approximates a true method failure rate.

Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women

ObjectiveTo evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen. Study designWe pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes. ResultsWe included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68–2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82−3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37−2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83−1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85−1.19]). Three percent of participants discontinued for a bleeding-related adverse event. ConclusionE4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns. Implications statementMost estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.

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.

Impact of aerobic fitness status, menstrual cycle phase, and oral contraceptive use on exercise metabolic flexibility

Metabolic flexibility is the ability to appropriately store or utilize substrates. Exercise such as high‐intensity interval exercise (HIIE) is also a robust test of one’s ability to shift between substrates to support metabolic demand. Menstrual cycle or oral contraceptive use may impact metabolic responses to exercise. Fitness status also plays an important role in metabolism. We assessed the impact of hormonal fluctuation and fitness status on exercise metabolism in women during HIIE. 25, healthy, active women (24.4±3.6yrs; 165.5±6.9 cm; 65.1±10.5 kg; 38.8±6.6mL/kg/min) experiencing a regular menstrual cycle (n=15) or using oral contraceptives (n=11) completed the study. Participants were split by aerobic fitness status (High: 43.7±4.7mL/kg/min; Low: 33.6±3.9mL/kg/min). Participants completed a baseline and counterbalanced HIIE sessions in the follicular (FOL) and luteal phase (LUT). FOL sessions took place 2‐7d after onset of menstruation or non‐active OC days. LUT sessions took place ~6‐8d following urine ovulation or third week of active OC pills. Exercise was performed on an electrically braked cycle ergometer. High intervals (H1‐H4) were 4x4 min intervals at the power output corresponding to 50% of the difference between the ventilatory threshold and VO2peak, separated with 3min of unloaded cycling (0W; low intervals). RPE and blood lactate assessed via finger stick were taken after each interval. There was no effect of menstrual cycle phase or oral contraceptive use on fat oxidation, carbohydrate oxidation or blood lactate. There was an effect of fitness status on fat oxidation in LUT and FOL (p=0.002). High fit women oxidized more fat during the full session (FOL: p=0.050, LUT: p=0.001), high intervals (FOL: p=0.048, LUT: p=0.001), and low intervals (FOL: p=0.032, LUT: p=0.024) during FOL and LUT, and recovery during LUT (p=0.033). Carbohydrate oxidation (g/kg; p=0.049) and AUC (p=0.024) were greater in high women during FOL, but not LUT. Blood lactate was significantly greater in low fit women during exercise interval H2 through recovery during FOL, but not LUT (p≤0.050). Total change in rate of fat oxidation (Δ g/kg/min) during HIIE intervals was greater in high vs low fitness during FOL (H2: p= 0.018, H3: p=0.004), and LUT (H1: p=0.041, H2: p=0.001, H3: p=0.001, H4: p=0.006). There was a correlation between exercise fat oxidation (g/kg) and lactate AUC (H1‐L4) during FOL (r=‐0.440, p=0.030; n=25) but not LUT (‐30 minute) (r=0.215, p=0.143; n=25). Our results reflect fitness status plays an important role in exercise fat oxidation, carbohydrate oxidation and blood lactate during HIIE in young women. High fitness women benefit from greater exercise metabolic flexibility than their low fit counterparts. These these differences may be unique to the menstrual cycle phase, with low fitness women having poorer exercise metabolic flexibility in the follicular phase.