Introduction
Worldwide, oral contraceptives are a popular choice among women of reproductive age to avoid unintended and mistimed pregnancies and to alleviate menstrual pain, premenstrual syndrome, abnormal uterine bleeding, and severe acne. Despite long-term experience with oral contraceptives since they were first introduced into the market in 1959, clinical studies on their influence on mental health and quality of life are still rare [
1‐
4]. Particularly, in adolescents and young women, the impact of sexual steroids, especially progesterone and estradiol, on depression has been controversially discussed, and it is unclear whether the development of mood changes and/or mental health disorders are clinically relevant side effects of hormone-based contraceptives [
5‐
7]. A large study including 6654 sexually active women aged 25–34 years conducted in the USA reported that hormonal contraception may reduce the levels of depressive symptoms among young women and thus may elicit a protective function [
8]. Similar results were reported from a small, cross-sectional Norwegian study in adult women showing a decreased likelihood of a current mood disorder in users of combined contraceptive preparations, whereas, in contrast, users of progestin-only agents experienced a deleterious effect [
9]. One small study in women aged 14–20 years found no significant changes in self-rated quality of life perception or depressive symptoms, despite the fact that both the number of days of menstrual bleeding and the use of analgetic medication to relieve menstrual pain were both reduced [
10]. In a double-blind, randomized, placebo-controlled trial in 340 young, healthy Swedish women aged 18–35 years, Zethraeus et al. demonstrated that a first-choice levonorgestrel-containing drug administered for the treatment of premenstrual symptoms resulted in a statistically significant reduction in general well-being, when compared to a placebo, but no statistically significant effects on depressive symptoms [
11].
However, a few important and well-conducted clinical studies suggested influences of hormone-based contraception on the development of depressive symptoms. A large cohort study conducted in Danish adolescents and young women demonstrated that the use of oral contraceptives was positively associated with higher frequencies of subsequent use of antidepressants and a first diagnosis of depression [
12]. Recently, the same group also reported that the use of hormonal contraception was positively associated with suicide attempt and suicide, which was particularly observed in adolescent women who experienced the highest relative risk [
13]. A similar relationship between the use of hormonal preparations and suicidal tendency was found in 27,067 women aged 20 years or older in data from the Korea National Health and Nutrition Examination Survey, KNHANES [
14].
Given the growing evidence that oral contraceptive use may impact on depressive mood and result in higher suicide rates, we considered whether also health-related quality of life known to be reduced in depressed subjects is likewise related to hormonal contraception. Therefore, the purpose of this study was to examine the association of hormone-based contraceptives with self- and parent-rated quality of life and mental health problems in girls aged 15–17 years. To this end, we performed a post hoc analysis using data from the representative and nationwide German Health Interview and Examination Survey for Children and Adolescents (Kinder- und Jugendgesundheitssurvey, KiGGS) to determine whether those that use oral contraceptives differ from their non-medicated counterparts in terms of mental well-being.
Discussion
This post hoc analysis was performed to test the clinically relevant hypothesis that female adolescents exposed to oral contraceptives had a reduced health-related quality of life and more psychopathological problems, which may precede the elevated suicidal tendency and increase in the number of suicide attempts recently reported in the literature for users of these drugs. Using data from the nationwide, representative KiGGS study, we found, however, that oral contraceptive use in German girls was unrelated to two well-established and independent psychometric measurements for mental well-being, namely health-related quality of life as measured by the KINDL-R and psychological distress and behavioral problems as measured by the SDQ. Neither KINDL-R nor SDQ scores were linked to the contraception status, regardless whether univariate comparisons or adjusted regression models were performed. The lack of a significant relationship between subjective parameters of mental well-being and hormonal contraception was independent of whether data from self- or parent-rated assessment were analyzed. In contrast, oral contraception was positively linked to a higher probability of taking psychotropic medication, in both univariate and multivariate analyses. Additionally, we observed that two somatic parameters, namely arterial blood pressure and serum 25(OH)D concentration, were elevated in users of oral contraceptives compared to non-users. Notably, these positive associations were observed in three out of four regression models calculated, whereas there was no evidence that blood pressure mediated indirect effects of oral contraception on serum 25(OH)D and vice versa, suggesting that the two factors functioned independently in the context of hormonal contraception.
Our data from the KiGGS study confirm previous results showing that hormonal contraception, especially among adolescents, was linked to a higher rate of subsequent use of antidepressants [
12]. There is evidence that daily ratings of mood and sexual interest follow hormonal changes during the menstrual cycle, since depression scores are highest during the premenstrual phase and lowest during the postmenstrual phase, whereas sexual interest peaked in the postmenstrual phase and bottomed out in the premenstrual phase [
34]. Unfortunately, however, information on the actual state of the menstrual cycle at the time of the study interview was not available in the KiGGS public use file.
Sex hormones act through binding to their specific nuclear receptors and are imported as transcriptionally active complexes into the nucleus to modulate gene induction in a ligand-dependent manner. Estrogen and progesterone receptors are widely expressed in the central nervous system, where they execute multiple and diverse non-reproductive functions. It is conceivable that the different steroid hormones and their metabolites affect brain excitability in a complex and regulated manner, as well as orchestrating menstrual cyclicity [
11].
In previous work using data from a subsample of the KiGGS study participants, our group as well as others demonstrated that low serum 25(OH)D levels were linked to more emotional and behavioral problems [
32,
33]. Likewise, in Iranian boys and girls with vitamin D-insufficiency or -deficiency (≤ 30 ng/mL), the prevalence of self-reported sadness or depression and poor sleep quality was significantly higher than in school students with normal vitamin D levels [
35]. An Italian study in 158 young women, aged 15–21 years, with premenstrual syndrome reported that vitamin D supplementation over 4 months can be regarded as an effective and convenient method for improving both quality of life and the intensity of mood disorders associated with severe hypovitaminosis D and symptoms of premenstrual syndrome [
36]. In a prospective, population-based birth cohort from South West England, Tolpannen et al. demonstrated that higher concentrations of 25(OH)D
3 assessed at a mean age of 9.8 years were associated with lower levels of depressive symptoms at age 13.8 years [
37].
In a prospective, population-based Canada-wide observational study, Brajic et al. demonstrated less hip region peak bone mineral density (BMD) accrual in adolescent users of combined hormonal contraceptives than in non-users [
38]. This finding confirms previous studies demonstrating that the physiological BMD increase is lower in adolescents with long-term use of birth-control pills than in non-users [
39‐
41]. Since the main effect of active vitamin D metabolites is to stimulate the absorption of calcium from the gut resulting in the mineralization of organic bone matrix, our finding of elevated vitamin D levels under hormonal contraception may not be fully unexpected. Given the positive correlation between serum vitamin D and quality of life, our observation linking oral contraceptive use to elevated vitamin D concentrations may be regarded as a compensatory mechanism which protects against a decline in mental health.
Similarly, elevations in blood pressure may account for the lack of decline in subjectively measured distress and mental well-being, as was observed here in users of hormonal contraceptives. Numerous studies have shown that long-term administration of oral contraceptives induced a mild elevation of systemic blood pressure also in late adolescence [
42,
43]. In a cross-sectional analysis on 1248 adolescents aged 17 years, the investigators of the Western Australian Pregnancy (Raine) study found that girls using oral contraceptives had 3.3 and 1.7 mmHg higher systolic and diastolic blood pressure, respectively, compared with non-users [
43]. In an important paper, Du et al. demonstrated that KiGGS study participants using hormonal contraceptives have a more unfavorable profile of cardiovascular risk factors and adverse health behaviors [
44]. The drug-related slight increase in systemic blood pressure may elicit an overt stress-dampening effect, which in users of oral contraceptives prevents a relevant decline in mental well-being probably by suppressing negative mood or masking depressive symptoms.
These findings should be interpreted in the light of several inherent limitations which resulted mainly from the cross-sectional study design, prohibiting any causal interpretation or conclusions on a temporal relationship. Data for this study were neither collected by the investigators for the purpose of this novel research question nor were data collection methods predetermined and controlled for complete and valid information on potential confounding factors. The public use file did not specify the nature or indication of the contraceptive and psychotropic drug medication and, in particular, no information was available on the distribution of antidepressants in current users and non-users of oral contraceptives. Du and co-authors reported that, in KiGGS participants, the most frequently used oral contraceptives (> 90%) were single-phase combined preparations with a fixed amount of ethinyl estradiol and progestin, with nearly one-half of users taking these drugs for a minimum of 1 year [
44]. Furthermore, there were no data on the season of study enrollment or on direct measurements of sunlight exposure known to affect dermal synthesis of vitamin D. An additional weakness of this post hoc study is that, due to the sample heterogeneity, the reported effect sizes were generally very small. However, the large sample size and the sophisticated method of sampling based on a random selection strategy allowed the detection of even weak associations which may be functionally relevant and should be verified in future studies using independent samples.
In summary, this large observational study found no evidence that the use of oral contraceptives in late adolescence is associated with a decline in health-related quality of life or mental well-being. This lack of a significant relationship between drug intake and mental health in this young cohort may be explained by the presence of compensatory pathways, and among them, serum vitamin D and blood pressure are interesting candidates for further investigations.
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