Importance of Monitoring Patients’ Hormonal Contraceptive Use

SPECIAL REPORT: HORMONES & PSYCHIATRY

Across all age groups, girls and women are at greater risk of developing depression than boys and men, with double the risk during pubertal onset and marked elevations in risk through young adulthood and the menopausal transition.¹ These periods are characterized by hormonal changes; women experience natural hormonal changes at menarche and menopause, and many women begin using hormonal contraceptives (HCs) during young adulthood when they become sexually active.² Notably, girls and women use HCs even if they are not sexually active because HCs can help reduce menstrual irregularity and alleviate symptoms related to menstrual periods.²

HCs can also improve mental health outcomes for some mood disorders associated with heightened sensitivity to hormonal fluctuations, such as premenstrual dysphoric disorder (PMDD), although the benefits appear to be specific to particular HC types.^3,4 Even outside of PMDD, some women report improvement in depressive symptoms after starting HC use,⁵ and data from some reviews of the literature on HCs and mood disorders conclude that there are no sweeping adverse effects for the general population.⁴

However, for some women, HC use does appear to be a risk factor for depression and other mood disorders.⁵ In this article, we discuss emerging research on HCs and depression, clarifying possible mechanisms and distinguishing between different HC types. We also suggest that long-acting reversible contraceptives (LARCs), such as hormonal intrauterine devices (IUDs), should be given greater consideration than they are currently. Our goal is not to discourage HC use, but rather to highlight potential risks that can be identified and monitored. We conclude with recommendations for best practices that can help psychiatrists and mental health clinicians mitigate the fact that, for some women, some types of HC use during some periods of time can exacerbate or precipitate the onset of depression.

HC Use and Depression Risk

One of the most comprehensive studies linking HC use to depression risk was conducted in Denmark.⁶ The sample included 1 million Danish women (age, 15-34 years) who had no prior diagnoses of depression, other major psychiatric disorders, or health conditions for which HC use is contraindicated. The research team tracked the medical records of these women for 19 years to determine whether starting HC use was associated with an increased incidence rate of subsequent depression diagnosis and prescription of antidepressants (relative to women in the same demographic groups who did not begin HC use). Most HC types were associated with greater incidence rates of depression diagnosis and prescription of antidepressants. However, the risk depended on age. Teenaged girls of 15 to 19 years demonstrated the highest increase in risk (1.8-3x depending on HC type); risk declined through women’s 20s and was lowest for women who began using HCs in their 30s. Similar patterns can be seen for first suicide attempts, again with the highest risk (2.06x) associated with starting HC use for adolescent girls ages 15 to 19.⁷

This research has received some criticism because epidemiological studies cannot determine that HC use causes depression, as other unmeasured factors might account for or attenuate the apparent risk.⁴ Indeed, the risk ratios in the same Danish sample are reduced when controlling for the effects of smoking and sexual history.⁸ However, those results could be reinterpreted to highlight preexisting factors that increase women’s vulnerability to depression when starting HC use. Moreover, if HC use, especially in adolescence, reliably co-occurs with other risk factors, HC use is still an important risk indicator that can be easily assessed, tracked, and considered in the overall patient profile to inform treatment.

Age is the most commonly reported risk factor for depression following HC use, with younger adolescent girls bearing the largest risks.^4-7 Other factors that appear to increase risk for depression following HC use are history of smoking, early age at sexual debut, and past sexual experience.⁹ Risk factors for depression (eg, family or personal history of mood-related disorders, adverse childhood experiences, stress) are also likely to increase the risk for depression following HC use.⁹ Finally, women with previous negative experiences with HCs may be vulnerable to depression when starting to take HCs again.¹⁰ However, there are many different HC types, and thus it may be possible for women with negative experiences with some HCs to find other HCs that work better for them.

Overview of Different HC Types

There is substantial heterogeneity in the types of HCs women use. Oral contraceptives (OCs) are the most commonly used² and are the most heterogenous category of HCs because they are formulated with at least 11 different types of synthetic progestins and have different dosage options. Moreover, although many OCs (“combined OCs”) also include ethinyl estradiol, some OCs do not. LARCs such as arm implants and hormonal IUDs are rapidly increasing in popularity.² Both arm implants and IUDs only contain progestins (no ethinyl estradiol), though they contain different types. HC types used less frequently include injectables (eg, Depo-Provera) and contraceptive patches or rings. See the Table for additional distinctions of HC types.

In relation to the research findings previously described, women with PMDD appear to particularly benefit from OCs formulated with the fourth-generation progestin drospirenone, and may experience worse outcomes if using HC methods that do not fully suppress endogenous hormone fluctuation (eg, IUD) or themselves fluctuate in progestin dosage (eg, multiphasic OCs).^3,4 In the Danish study on depression,⁶ the highest increase in depression risk was for adolescent girls who began using hormonal IUDs as well as contraceptive patches or rings. Across age and outcome, progestin-only OCs have been linked with greater depression risk relative to combined OCs.^6,7

Biopsychosocial Mechanisms

Although the mechanisms through which HC use is linked with increased depression risk are not well understood, 2 plausible and complementary mechanisms have been proposed: dysregulation of stress reactivity and reductions in positive affect. Stress researchers have known that OC use reliably “blunts” women’s cortisol response to acute stress since the 1990s.¹¹ However, the rise of cortisol in response to a stressor is important for managing stress and downregulating inflammatory processes. A blunted cortisol response means that cortisol is not responding as it should and is itself a biomarker of depression.¹² Due to their atypical cortisol response, women taking OCs are routinely excluded from studies on stress,¹³ creating a large gap in knowledge about the effects of OC use on stress-related processes.

Probing this gap, our team compared stress reactivity between women taking OCs and naturally cycling (NC) women.¹⁴ We found that women taking OCs self-reported elevated stress levels following an acute psychosocial stressor. Although those taking OCs showed small changes in cortisol, when cortisol did rise, it was accompanied by decreases in mood positivity, a pattern not seen in NC women. Together, these results indicate that the stress response systems of women taking OCs may not be helping them to effectively manage stressors. Given the links between stress and depression, maladaptive stress coping could be one mechanism through which HC use can increase depression risk in some.

Research has only just begun to examine whether IUDs also affect women’s stress reactivity. Our team compared cortisol reactivity among women with an IUD, those taking an OC, and NC women.¹⁵ We found that women using both IUDs and OCs had blunted cortisol responses compared with NC women. Another research group has also documented the blunted cortisol response among women with IUDs.¹⁶ This finding suggests that, although released locally and in a relatively low dose, the IUD’s progestins have systemic effects, including on the hypothalamic-pituitary-adrenal axis.

Given that social support can buffer against the negative effects of stress, we also compared women’s desire for social connection after the stressor.¹⁵ Women who take OCs showed a reduced desire for social connection compared with NC women, suggesting that those taking OCs may be vulnerable to depression because they may be less likely to lean on their support network during times of stress. However, women with IUDs did not differ from NC women. The 2 HC types thus similarly dysregulated the cortisol response, but only OC takers showed decreases in social support seeking. Overall, rather than excluding women taking HCs from studies on stress, research should focus on understanding how different types of HCs may differentially impact various stress-related responses.

Although many clinicians have assumed that a link between HC use and depression would occur via increases in negative mood, especially during the premenstrual phase of women’s cycles, mounting evidence suggests that the impacts of HCs on mood might occur via reductions in positive processes.⁵ Data in one study showed reductions in positive affect over the first 3 months of OC use that were not seen in a control group of NC women.¹⁷ Likewise, our team’s preliminary findings suggest that, compared with NC women, those taking HCs may use fewer positive coping strategies and experience a blunted relationship between receiving social support and positive affect.

Concluding Thoughts

This emerging research on HCs and mood-related disorders has sparked public discourse. The research on unintended consequences of HC use is heterogeneous,^4,5 with the clearest message being that effects of HC use on mood-related outcomes differ between women, HC types, and situations. Consequently, clinicians need to be well informed on emerging research so that adolescent girls and women are not relying upon social media influencers to help them make decisions about HC use. As one step toward this, the National Academies of Sciences, Engineering, and Medicine recently convened a workshop titled “Essential Health Care Services Related to Anxiety and Mood Disorders in Women,” which sought to provide recommendations to the US Health Resources and Services Administration regarding women’s mental health care services.¹⁸ This meeting brought together diverse stakeholders to discuss solutions to women’s increased risk for mood-related disorders. Many clinicians in attendance were unaware that HC use could alter their patient’s depression risk. Although policy-level changes are far out on the horizon, clinicians can make changes individually today to improve their care for adolescent girls and women.

A critical yet easy change psychiatrists can make is to directly assess HC use. One way to do so is to link to patients’ medical records. Additionally, it is important to have conversations with patients about current HC use, changes to their HC use, and plans to begin taking HCs for established clients with preexisting mood disorders. Conversations can help women identify HC use as a potential contributor to positive or negative changes to their mood and help clinicians identify this risk factor in situations when medical records may not be comprehensive or transfer between health systems. This probing is especially important for adolescent girls and women under 25. Moreover, clinicians should specifically ask about non-OC use, because women may not mention LARCs when asked about medications they are taking. Women may have difficulty making the association between changes in mood and use of HCs, because depressive symptomology onset tends to occur between 3 and 12 months after starting HCs.⁶ Making the association may be particularly unlikely for LARCs, because once they are successfully placed, patients rarely think about them. Further, none of the pamphlets for currently available hormonal IUDs mention mental health risks or systemic effects related to stress responses, and they present progestins as “local” and “low dose,” potentially insinuating that women need not be observant of changes in their mental health.

The Figure presents our suggestions for mindful monitoring of mood for new and current patients who may have recently started taking HCs or plan to start taking them in the near future. During the first 3 to 12 months of HC use, clinicians should regularly assess patients for mood-related changes that may occur, especially if they possess other known risk factors for depression. If mood-related symptoms emerge, psychiatrists and mental health clinicians should inform patients about different HC types and discuss the costs and benefits of remaining on the current HC vs potentially switching to another HC type. The use of HCs offers many benefits to women, and many women will not experience mood-related adverse effects or worsening of depression symptoms. However, engaging in direct communication about HC use can help flag risk factors and vulnerabilities that are currently poorly considered, thereby informing the overall patient profile and improving the comprehensive treatment plan.

Dr Makhanova is an associate professor in the Department of Psychological Science at the University of Arkansas in Fayetteville.

Ms Joslin is a PhD candidate in the Department of Psychological Science at the University of Arkansas in Fayetteville.

Dr Mengelkoch is a postdoctoral fellow in the Department of Psychiatry and Biobehavioral Sciences at the University of California, Los Angeles.

Acknowledgement: We thank Ana Baca for her assistance in designing the Figure.

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