Adolescent oral contraceptive use predicts lasting risk for adulthood depression

Adolescent use of oral contraceptives increases adult vulnerability to depression

Following up on previous evidence that adolescent use of oral contraceptives may increase the risk of depression in adulthood, the authors of a study published in The Journal of Child Psychology and Psychiatry investigated whether oral contraceptives in adolescence promoted a long term prevalence for depression in adulthood. This is a compelling question since the synthetic forms of estrogen and/or progesterone in oral contraceptives suppress endogenous production of those hormones and testosterone; these have important brain in addition to reproductive effects. Their findings show that adolescence may be a vulnerable period during which OC use could increase the risk for depression regardless of current use.

While the benefits of OC use for adolescent and adult women have been well documented (e.g. Lindberg, Santelli, & Desai, 2016), it is crucial to also understand their potential side effects in the short and long terms. While a number of prior studies have investigated short-term associations between OC use and depression risk (generally within the subsequent year), the present study focuses on whether use of OCs might have lasting effects on depression risk, potentially even years later.

Earlier evidence for oral contraceptive use and later depression

The authors note evidence from earlier studies, including these:

Indeed, a recent prospective population-based analysis of over 1 million women (all women living in Denmark aged 15–34 years) indicates that, in the short term, use of OCs or other forms of hormonal contraceptives is associated with increased use of antidepressants and a higher likelihood of a first diagnosis of depression; the observed relationship was strongest in adolescents (Skovlund et al., 2016).

In another prospective population-based study on over 800,000 women aged 12–30 years residing in Sweden, adolescents, but not young adults, who used hormonal contraception were more likely to use other drugs commonly prescribed for mental health impairments (anxiolytics, hypnotics and sedatives) (Zettermark, Vicente, & Merlo, 2018).

These results are further supported by two large-scale cross-sectional studies, which showed increased use of antidepressants (Lindberg, Foldemo, Josefsson, & Wirehn, 2012) and higher rates of diagnosed depression (McKetta & Keyes, 2019) in adolescent OC users in bivariate associations.

Biological mechanisms of vulnerability

Especially during critical developmental periods the gonadal hormones have an organizing effect on brain development that can result in long-term changes. These hormones also impact the hypothalamic-pituitary-adrenal axis and limbic regions known to be dysregulated in depression. Furthermore...

...a recent study showed that earlier pubertal timing, which is tightly coupled with exposure to gonadal hormones (Shirtcliff, Dahl, & Pollak, 2009), prospectively predicted altered white matter microstructure in the uncinate fasciculus and the cingulum bundle at age 19 (Chahal et al., 2018); both...have been linked to depression risk (reviewed in Bracht, Linden, & Keedwell, 2015).

Furthermore, both oestradiol and testosterone levels in adolescent women predicted white matter and right amygdala size measured 2 years later in a prospective study, independent of age (Herting et al., 2014).

More than three times the risk for major depression

The authors examined data for 1,236 women, 561 of whom first used oral contraceptives in adolescence, 353 first used OCs as adults, and 322 had never them. From among these, 131 qualified for a diagnosis of major depressive disorder (MDD). The findings were eye-opening:

In a U.S. representative sample of 1,236 women, we found that prior OC use in adolescence predicted a higher 1-year prevalence of MDD in adulthood compared with both women who had never used OCs and women who had only started using OCs after adolescence. Specifically, compared with women who had used OCs during adolescence, women who had never used OCs had 0.31 times the odds (95% CI = 0.16–0.60) of meeting the criteria for MDD within the past year and women who only started using OCs in adulthood had 0.54 times the odds (95% CI = 0.30–0.95). These disparities held after controlling for potential confounds in propensity score weighted models and in a subsample of women who had their sexual debut in adolescence. Our findings are consistent with a recent large-scale prospective study showing that OC use in adolescence is associated with increased depression (Skovlund et al., 2016).

Adolescence is clearly a sensitive period for exposure to oral contraceptive hormones:

Critically, by indicating that women who had used OCs during adolescence were at heightened risk for depression in adulthood even when controlling for current OC use, our findings suggest that adolescence may represent a sensitive period during which the use of OCs could increase women’s likelihood to develop depression until years after first exposure. This interpretation is in accordance with the abundant evidence from animal models showing that gonadal hormones can cause long-lasting changes in brain and behaviour especially during critical developmental periods such as puberty/adolescence (Berenbaum & Beltz, 2011; Schulz et al., 2009).

Urgent need for further insight

Additionally, the promotion of hypothyroidism by the blunt pituitary (TSH) suppression of oral contraceptives is an additional concern not addressed in this study. The hypothyroid effect on frontal lobe activation can also contribute to depression. The authors conclude:

In this study, we found that women who had used OCs during adolescence show an increased risk to have a depressive episode in adulthood, years after first exposure. Critically, these findings were not accounted for by a large number of third variables that have previously been used to explain observed relationships between OC use and depression.

While providing women of all ages with access to effective methods of birth control is and should continue to be a major global health priority (Temmerman, Khosla, Laski, Mathews, & Say, 2015), the presented findings reveal an urgent need for future studies to address whether there is indeed a causal link between use of OCs and other forms of hormonal contraception in adolescence and the risk of developing depression and other psychopathologies in the short and long terms.