Dataset Information

Oral contraceptives and the serotonin 4 receptor: a molecular brain imaging study in healthy women.

ABSTRACT:

Objective

Sex steroid hormones potently shape brain functions, including those critical to maintain mental health such as serotonin signaling. Use of oral contraceptives (OCs) profoundly changes endogenous sex steroid hormone levels and dynamics. Recent register-based studies show that starting an OC is associated with increased risk of developing depression. Here, we investigate whether use of OCs in healthy women is associated with a marker of the serotonin system in terms of serotonin 4 receptor (5-HT4R) brain imaging.

Methods

[¹¹C]SB207145-PET imaging data on 53 healthy women, of whom 16 used OCs, were available from the Cimbi database. We evaluated global effects of OC use on 5-HT4R binding in a latent variable model based on 5-HT4R binding across cortical and subcortical regions.

Results

We demonstrate that OC users have 9-12% lower global brain 5-HT4R binding potential compared to non-users. Univariate region-based analyses (pallidostriatum, caudate, hippocampus, amygdala, anterior cingulate cortex, and neocortex) supported the global effect of OC use with the largest difference present in the hippocampus (-12.8% (95% CI [-21.0; -3.9], P_corrected = 0.03).

Conclusion

We show that women who use OCs have markedly lower brain 5-HT4R binding relative to non-users, which constitutes a plausible molecular link between OC use and increased risk of depressive episodes. We propose that this reflects a reduced 5-HT4R gene expression, possibly related to a blunted ovarian hormone state among OC users.

SUBMITTER: Larsen SV

PROVIDER: S-EPMC7586815 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Oral contraceptives and the serotonin 4 receptor: a molecular brain imaging study in healthy women.

Larsen S V SV Köhler-Forsberg K K Dam V H VH Poulsen A S AS Svarer C C Jensen P S PS Knudsen G M GM Fisher P M PM Ozenne B B Frokjaer V G VG

Acta psychiatrica Scandinavica 20200721 4

<h4>Objective</h4>Sex steroid hormones potently shape brain functions, including those critical to maintain mental health such as serotonin signaling. Use of oral contraceptives (OCs) profoundly changes endogenous sex steroid hormone levels and dynamics. Recent register-based studies show that starting an OC is associated with increased risk of developing depression. Here, we investigate whether use of OCs in healthy women is associated with a marker of the serotonin system in terms of serotonin ...[more]

PMID: 33314049

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Project description:BackgroundPrucalopride is a selective, high-affinity, 5-hydroxytryptamine 4 (5-HT4) receptor agonist, which is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Women of childbearing potential, many of whom will be using oral contraceptives, comprise a large proportion of patients seeking medical therapy for constipation.ObjectiveThe aim of this study was to evaluate the effect of prucalopride on the absorption and steady-state pharmacokinetics of oral contraceptives in healthy women.MethodsSixteen women (aged 18-45 years) were enrolled in this open-label, two-way crossover trial (ClinicalTrials.gov identifier: NCT01036893) and given two 5-day treatments with a once-daily oral contraceptive (ethinylestradiol 0.035 mg + norethisterone 1 mg), alone and in combination with prucalopride 2 mg once daily. Treatments were separated by a 7 ± 2-day washout period. On days 1 and 5, blood samples were obtained pre-dose and at regular intervals post-dose up to 24 and 48 hours, respectively, to determine ethinylestradiol and norethisterone plasma concentrations. Prucalopride plasma concentrations were determined pre-dose and 3 hours post-dose on days 1 and 5, and 24 hours post-dose on day 6. Safety was assessed.ResultsThirteen participants completed the study. One participant was thought to be non-compliant on days 3 and/or 4, and was excluded from the day 5 analysis. On days 1 and 5, maximum plasma concentrations of both oral contraceptive constituents were attained in ~1 hour and were unaffected by prucalopride administration. On day 5, steady-state prucalopride and oral contraceptive concentrations had been achieved. Prucalopride did not affect the pharmacokinetics of the oral contraceptives: point estimates for the maximum plasma concentration and area under the plasma concentration-time curve values and their associated 90 % confidence intervals were contained within predefined equivalence limits (80-125 %). Prucalopride was well tolerated, with a safety profile consistent with those observed in previous studies.ConclusionCo-administration of prucalopride with an oral contraceptive did not result in any clinically meaningful pharmacokinetic interactions and was well tolerated.

Project description:Importance:Women are at higher risk of drug-induced torsade de pointes (TdP) than men. Androgens are protective. Influence of oral contraception on drug-induced TdP and QT prolongation is controversial. Objective:To determine if the extent of sotalol-induced corrected QT (QTc) prolongation and specific T-wave morphological changes, which are biomarkers for the risk of drug-induced TdP, differ in patients according to the androgenic activity of the type of oral contraceptive (OCs) they take compared with patients who took no pills. Design, Setting, and Participants:A cohort of 498 healthy, nonmenopausal women received 80 mg of oral sotalol, a drug with known risk of drug-induced TdP, during this study in a clinical investigation center. The participants also took either no oral contraception or received OCs with different types of progestin: levonorgestrel (which has high androgenic potency), desogestrel or gestodene (which has intermediate androgenic potency), or drospirenone (which has antiandrogenic properties). Women were enrolled from February 2008 to February 2012, and data analysis took place from September 2014 to May 2018. Main Outcomes and Measures:Electrocardiographic changes 3 hours after sotalol administration. Results:A total of 137 women received levonorgestrel, 41 received desogestrel, 51 received gestodene, and 62 received drospirenone; another 207 received no OCs. Baseline QTc duration, plasma sotalol levels, and potassium levels did not significantly differ among groups. However, 3 hours after sotalol exposure, QTc prolongation was greater in women taking drospirenone (mean [SD] increase, 31.2 [12.6] milliseconds from baseline) than in women taking no OCs (mean [SD] increase, 24.6 [12.5] milliseconds; P?=?.005) or those taking levonorgestrel (mean [SD] increase, 24.2 [13.7] milliseconds; P?=?.005). The frequency of sotalol-induced T-wave alteration was higher in women taking drospirenone (n?=?13 of 61 [21.0%]) than those taking levonorgestrel (n?=?20 of 137 [14.6%]) or women taking no OCs (n?=?24 of 207 [11.6%]; P?=?.01). Disproportionality analysis using the European pharmacovigilance database showed a higher reporting rate of OC-induced prolonged QT and ventricular arrhythmias in women taking drospirenone than levonorgestrel (drug-induced long QT syndrome: reporting odds ratio [ROR], 6.2 [95% CI, 1.3-30.8]; P?=?.01; ventricular arrhythmia: ROR, 3.3 [95% CI, 1.7-6.3]; P?<?.001). Conclusions and Relevance:Contraceptive pills are associated with variable drug-induced alterations of ventricular repolarization in healthy nonmenopausal women. Drospirenone, an antiandrogenic pill, was associated with increased sotalol-induced QTc prolongation, although absolute QTc prolongation was modest. This finding was supported by the European pharmacovigilance database, which showed a higher reporting rate of suspected OC-induced ventricular arrhythmias on drospirenone compared with levonorgestrel. More data are required on whether antiandrogenic OCs lead to clinically significant adverse events in patients taking QTc-prolonging drugs.

Project description:BACKGROUND:Little is known about how the menstrual cycle affects gastrointestinal function and self-reported stress in young, healthy women taking oral contraceptives (OC). This study prospectively characterized gastrointestinal function and symptoms on each day throughout the menstrual cycle. METHODS:Healthy women aged 18-35?years (n?=?78) who took OC participated in the 5-week observational study. Stool frequency, self-reported stress, stool form measured by the Bristol Stool Form Scale (BSFS), and gastrointestinal symptoms measured by a modified version of the Gastrointestinal Symptom Rating Scale (GSRS) were assessed daily. GSRS scores were reported (1?=?no discomfort at all, 7?=?very severe discomfort) and were averaged for individual syndrome scores or summed for the total score. The validated, weekly version of the GSRS was completed at two time points to reflect menstruation and 1?week prior to menstruation (n?=?72). Outcomes were analyzed in linear mixed models with the Dunnett's post hoc test against day 1 of menstrual bleeding or with nonparametric tests. RESULTS:Daily stress (P?=?0.0018), BSFS score (P?=?0.0493), stool frequency (P?=?0.0241), abdominal pain (P?<?0.0001), diarrhea (P?=?0.0022), constipation (P?=?0.0446), reflux (P?=?0.0193), and indigestion (P?<?0.0001) all varied significantly by the day of the menstrual cycle. Dunnett's post hoc tests showed that scores (mean?±?SEM) on the first day of bleeding (day 1) for daily abdominal pain (2.6?±?0.2), diarrhea (1.7?±?0.1), and indigestion (2.1?±?0.2) symptoms were higher than scores on all other days of the menstrual cycle (P?<?0.05) with scores not on day 1 falling under 1.5, or between no discomfort at all and slight discomfort. Reflux, stool frequency, BSFS, self-reported stress, and constipation were higher on day 1 (P?<?0.05) than on 12, 8, 6, 4, and 2 other days of the menstrual cycle, respectively. The median (IQR) GSRS score was higher during the week of menstruation than the week prior to menstruation for diarrhea [1.50 (1.00-2.33) vs 1.33 (1.00-2.00), P?=?0.002] and abdominal pain [2.00 (1.33-2.67) vs 1.67 (1.33-2.33), P?=?0.011] syndrome scores. CONCLUSION:Bowel habits appear to vary across the menstrual cycle and suggest more gastrointestinal discomfort on day 1 of menstrual bleeding in healthy women taking OC. Future interventional studies could identify ways to improve gastrointestinal symptoms in healthy women during menstruation.

Dataset Information

Oral contraceptives and the serotonin 4 receptor: a molecular brain imaging study in healthy women.

Objective

Methods

Results

Conclusion

Publications

Oral contraceptives and the serotonin 4 receptor: a molecular brain imaging study in healthy women.

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