Research on the effect of oral contraceptive (OC) use on the risk of depression shows inconsistent findings, especially in adult OC users. One possible reason for this inconsistency is the omission of women who discontinue OCs due to adverse mood effects, leading to healthy user bias. To address this issue, we aim to estimate the risk of depression that is associated with the initiation of OCs as well as the effect of OC use on lifetime risk of depression.
Methods
This is a population-based cohort study based on data from 264,557 women from the UK Biobank. Incidence of depression was addressed via interviews, inpatient hospital or primary care data. The hazard ratio (HR) between OC use and incident depression was estimated by multivariable Cox regression with OC use as a time-varying exposure. To validate causality, we examined familial confounding in 7,354 sibling pairs.
Results
We observed that the first 2 years of OC use were associated with a higher rate of depression compared to never users (HR = 1.71, 95% confidence interval [CI]: 1.55-1.88). Although the risk was not as pronounced beyond the first 2 years, ever OC use was still associated with an increased lifetime risk of depression (HR = 1.05, 95% CI: 1.01-1.09). Previous OC use were associated with a higher rate of depression compared to never users, with adolescent OC users driving the increased hazard (HR = 1.18, 95% CI: 1.12-1.25). No significant association were observed among adult OC users who had previously used OCs (HR = 1.00, 95% CI: 0.95-1.04). Notably, the sibling analysis provided further evidence for a causal effect of OC use on the risk of depression.
Conclusions
Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life. Our results are consistent with a causal relationship between OC use and depression, as supported by the sibling analysis. This study highlights the importance of considering the healthy user bias as well as family-level confounding in studies of OC use and mental health outcomes. Physicians and patients should be aware of this potential risk when considering OCs, and individualized risk-benefit assessments should be conducted.
PMID 37303201 37303201 DOI 10.1017/S2045796023000525 10.1017/S2045796023000525 Johansson et al. 2023, Johansson 2023
Cite this article
Johansson, T., Larsen, S. V., Bui, M., Ek, W., Karlsson, T., & Johansson, Å. (2023). Population-based cohort study of oral contraceptive use and risk of depression. Epidemiology and psychiatric sciences, 32, e39. https://doi.org/10.1017/S2045796023000525
Johansson T, Larsen SV, Bui M, Ek W, Karlsson T, Johansson Å. Population-based cohort study of oral contraceptive use and risk of depression. Epidemiol Psychiatr Sci. 2023;32:e39. doi:10.1017/S2045796023000525
Johansson, Therese, et al. "Population-based cohort study of oral contraceptive use and risk of depression." Epidemiology and psychiatric sciences, vol. 32, 2023, pp. e39.
Combined oral contraceptives (COCs) possess the ability to alter the normal composition of the gut microbiome and the permeability of the gastrointestinal (GI) tract, which may cause both gut-related and non-gut-related complications. The gut-estrogen axis examines the relationship between estrogens (particularly the active form, estradiol) and the gastrointestinal system and can be attributed to the maintenance of the estrobolome and circulating estradiol levels. The gut-brain axis involves the relationship between the brain and the gastrointestinal system and can be attributed to the gut microbiome in relation to the enteric nervous system (ENS) and serotonin levels. Overall, the introduction of exogenous hormones into an endogenous environment alters the normal balance of both hormones and bacteria. Currently, there is a gap in knowledge regarding the link between COCs and mental health complications such as anxiety and depression, and the diversity in these complications may be related to different types of COCs, their composition, and variations in study populations. This article reviews existing evidence from animal and human studies on the role of COCs in the development of mental health issues through their impact on the gut microbiome.
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. DESIGN, SETTING, 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.
contraception/oral-contraceptives/metabolic-effectstherapeutics/hormonal-agents/estrogen-preparations
Open Access
Current use of combined hormonal contraceptives worsens glucose tolerance and increases the risk of type 2 diabetes mellitus at late fertile age, but the impact of their former use on the risk of glucose metabolism disorders is still controversial. MATERIAL AND This was a prospective, longitudinal birth cohort study with long-term follow-up consisting of 5889 women. The cohort population has been followed at birth, and at ages of 1, 14, 31 and 46. In total, 3280 (55.7%) women were clinically examined and 2780 also underwent a 2-h oral glucose tolerance test at age 46. Glucose metabolism indices were analyzed in former combined hormonal contraceptive users (n = 1371) and former progestin-only contraceptive users (n = 52) and in women with no history of hormonal contraceptive use (n = 253). Compared with women with no history of hormonal contraceptive use, those who formerly used combined hormonal contraceptives for over 10 years had an increased risk of prediabetes (odds ratio [OR] 3.9, 95% confidence interval [CI]: 1.6-9.2) but not of type 2 diabetes mellitus. Former progestin-only contraceptive use was not associated with any glucose metabolism disorders. The results persisted after adjusting for socioeconomic status, smoking, alcohol consumption, parity, body mass index and use of cholesterol-lowering medication. Former long-term use of combined hormonal contraceptives was associated with a significantly increased risk of prediabetes in perimenopausal women, which potentially indicates a need of screening for glucose metabolism disorders in these women.
Assess the association between combined hormonal contraceptives (CHC) use and musculoskeletal tissue pathophysiology, injuries or conditions.
Systematic review with semiquantitative analyses and certainty of evidence assessment, guided by the Grading of Recommendations Assessment, Development and Evaluation approach. Data Sources: MEDLINE, EMBASE, CENTRAL, SPORTDiscus, CINAHL searched from inception to April 2022. Intervention and cohort studies that assessed the association between new or ongoing use of CHC and an outcome of musculoskeletal tissue pathophysiology, injury or condition in postpubertal premenopausal females. Across 50 included studies, we assessed the effect of CHC use on 30 unique musculoskeletal outcomes (75% bone related). Serious risk of bias was judged present in 82% of studies, with 52% adequately adjusting for confounding. Meta-analyses were not possible due to poor outcome reporting, and heterogeneity in estimate statistics and comparison conditions. Based on semiquantitative synthesis, there is low certainty evidence that CHC use was associated with elevated future fracture risk (risk ratio 1.02-1.20) and total knee arthroplasty (risk ratio 1.00-1.36). There is very low certainty evidence of unclear relationships between CHC use and a wide range of bone turnover and bone health outcomes. Evidence about the effect of CHC use on musculoskeletal tissues beyond bone, and the influence of CHC use in adolescence versus adulthood, is limited. Given a paucity of high certainty evidence that CHC use is protective against musculoskeletal pathophysiology, injury or conditions, it is premature and inappropriate to advocate, or prescribe CHC for these purposes. This review was registered on PROSPERO CRD42021224582 on 8 January 2021.