An observational study in Hormonal Contraception, sponsored by University Hospital Tuebingen. Enrolling by invitation at 1 site in Germany. Open to female participants aged 18 Years to 40 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-03-01.
Sponsored by University Hospital Tuebingen · Observational
For almost 60 years, millions of women globally have relied on oral contraceptive (OC) pills for pregnancy prevention and addressing menstrual irregularities. However, 4-10% of users experience mood-related side effects such as depression and anxiety, often leading to discontinuation of OC use. Previous studies also indicate that OC usage may lead to chronic alterations in brain structure and the regulation of the hypothalamic-pituitary-adrenal axis, a system involved in regulating stress responses. In the proposed study the investigators aim to investigate in more detail how women who start taking oral contraception (OC) and women who stop taking OC differ in their stress reactivity and their mood from long-term OC users. Furthermore, assessing hormones will help to shed light on the connection between OC, stress reaction, sex hormones and the brain. To achieve this, individual biomarkers will be evaluated, including changes in brain anatomy, functional responses and connectivity during acute psychosocial stress and early changes in mood and well-being through ambulatory assessment.
The study will use a longitudinal design with two time points to compare three groups, the women who want to start taking the pill, the women who want to stop taking it, and those who are long-term users of the pill. They will be exposed to a psychosocial stress induction task (Montreal Imaging Stress Task; MIST) in functional magnetic resonance imaging (fMRI) to get mechanistic insights. Measurements will be done before and during OC use (group 1; OC-Starters) and during and after the termination of OC use (group 2; OC-Stoppers). Therefore, at the first time point (T1) of the measurements, the OC-Starter will be in their early follicular phase while the OC-Stopper will be in their active pill intake weeks. At the second time point (T2), the OC-Starter will be in the active pill intake weeks and the OC-Stopper in their early follicular phase. The OC-Long-Term users (group 3) will be in their active pill intake weeks at both measurement time points (T1 and T2). Along with measuring heart rate, skin conductance and pulse oximetry as indicators of stress, saliva samples will be collected during the assessment in the fMRI to determine cortisol levels. Hormones (e.g., estradiol, ethinylestradiol, testosterone, and their precursor steroids and metabolites) will be assessed from blood samples at both time points (T1 and T2). Hair samples are collected at both measurement time points (T1 and T2) from the study participant to record the cumulative cortisol secretion of the past 3 months (= 3cm of hair) as a marker for chronic stress. For this purpose, a small strand of hair on the back of the head of the participant will be cut as close to the scalp as possible. These measures will be analyzed alongside individual markers of stress responsivity derived from brain imaging and questionnaires on stress and emotion regulation. These trait-like measures will be assessed at baseline (T1) and three months after the start/end of OC use (T2) to evaluate long-term changes. Additionally, at T1 and T2, medically trained personnel will conduct transvaginal ultrasound examinations to visualize the female reproductive organs and assess any organic changes resulting from OC usage. After the first time point T1, ambulatory assessments will be utilized over three months in all groups to assess daily fluctuations in stress and mood over the transition period starting or stopping OC and to ensure ecological validity of mood and stress reactivity. For this purpose, changes in average mood and mood variations will be quantified by collecting self-reports of daily hassles. A voluntary follow-up questionnaire is then used after six months (T3) to assess long-term changes in mood and stress reactivity.
University Hospital Tuebingen is the lead sponsor of 476 studies on the registry; 104 are open to participants now.
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community sample
Exclusion Criteria:
Women who start taking oral contraception
Other: Combined oral contraception
Women who stop taking oral contraception
Other: Discontinuation of a combined oral contraception
Women who use oral contraception continuously
Women, who want to start taking birth control pills will get a prescription for oral contraception at the discretion of their own attending physician
Cessation of the use of combined oral contraceptives
Stress-induced changes in mood
Change in mood after stress inductions measured by ratings of positive and negative affect before and after the stress task will be measured with the PANAS questionnaire (scale 1-5). It will be measured twice three months apart; each time: 60min before stress onset, just before stress onset, immediately after stress, 40min after stress onset, 60min after stress onset, 90min after stress onset.
Time frame: Pre medication vs. 3 months after medication
Stress-induced changes in the subjective experience of stress
Change in subjective stress experience after stress inductions measured by stress items before and after the stress task will be measured with a visual analog scale (1-10). It will be measured twice three months apart; each time: 60min before stress onset, just before stress onset, immediately after stress, 40min after stress onset, 60min after stress onset, 90min after stress onset.
Time frame: Pre medication vs. 3 months after medication
Stress-induced changes in brain response
BOLD response to stress (changes in amplitude) within regions associated with stress reactivity and regulation (amygdala, hippocampus, prefrontal cortex, anterior cingulate cortex (ACC), middle frontal gyrus (MFG), right superior temporal gyrus (STG), insula, striatum, and praecuneus) will be quantified using fMRI to assess differences between stress vs. control conditions during the stress task.
Time frame: Pre medication vs. 3 months after medication
Stress-induced changes in functional connectivity
Functional connectivity will be assessed within regions associated with emotional processing (amygdala, hippocampus, prefrontal cortex, hypothalamus, striatum, insula) using fMRI to assess differences between stress vs. control conditions during the stress task.
Time frame: Pre medication vs. 3 months after medication
Stress-induced changes in skin conductance
Skin conductance \[μS\] during stress condition vs. no stress condition as indicators of stress during fMRI
Time frame: Pre medication vs. 3 months after medication
Stress-induced changes in pulse
Pulse oximetry during stress condition vs. no stress condition as indicators of stress during fMRI
Time frame: Pre medication vs. 3 months after medication
Stress-induced changes in cortisol
Salivary cortisol levels to determine cortisol levels \[μg/dL or nmol/L\] during stress condition vs. no stress condition and baseline as indicators of stress/Hypothalamic-Pituitary-Adrenal-axis activation. It will be measured twice three months apart; each time: 60min before stress onset, just before stress onset, immediately after stress, 40min after stress onset, 60min after stress onset, 90min after stress onset.
Time frame: Pre medication vs. 3 months after medication
Oral Contraceptive induced changes in average mood during transition phase
Changes in positive and negative mood ratings (5 mood and 5 stress items, scale 1-10), measured with ecological momentary assessment after starting vs. stopping oral contraceptive intake.
Time frame: Over the course of three months regularly (30 times in total), about 5 minutes per day
Oral Contraceptive induced changes in hormone levels
Changes in endogenous and synthetic hormone levels will be assessed from blood samples before and after starting vs. stopping oral contraceptive use.
Time frame: Pre medication vs. 3 months after medication
Oral Contraceptive induced changes in brain volume (structure)
Changes operationalized with a structural T1 scan of the whole brain before and after starting vs. stopping oral contraceptive use.
Time frame: Pre medication vs. 3 months after medication
Oral Contraceptive induced changes in chronic stress
Associations of chronic stress, assessed via hair cortisol measures and chronic stress questionnaire (Trier Inventar of Chronic Stress - TICS; value range = \[0 228\]; higher outcome relates to a higher chronic stress rating) with oral contraception and stress reactivity. To record the cumulative cortisol secretion of the past 3 months (= 3cm of hair) as a marker for chronic stress, a small strand of hair on the back of the head of the participant will be cut as close to the scalp as possible.
Time frame: Pre medication vs. 3 months after medication
Oral Contraceptive induced organic changes in reproductive organs
Changes operationalized with a transvaginal ultrasound to examine the female reproductive organs (uterus, fallopian tubes and ovaries) before and after starting vs. stopping oral contraceptive use.
Time frame: Pre medication vs. 3 months after medication
Oral Contraceptive induced long-term changes in mood
Changes in positive and negative mood ratings measured with the PANAS questionnaire (scale 1-5)
Time frame: Six months after medication change
Plan to share: Yes — After the publication of the key results of the study, all anonymized research data, including imaging data, will be made publicly available (e.g., at openfmri.org).
Supporting information: Study protocol, Sap, Icf, Analytic code
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University Hospital Tuebingen