Hormonal Contraceptive Use and Levels of Depressive Symptoms
Hormonal Contraceptive Use and Levels of Depressive Symptoms
In the present study, we found a protective association between hormonal contraceptive use and depressive symptoms, as well as suicide attempts, in a population-based sample of young, sexually active US women. These associations persisted even after controlling for all measured factors related to health and lifestyle, including prior depressive symptoms and hormonal contraceptive use. The study documented this effect among these women at 2 different life stages, once in the early 20s and once in the late 20s/early 30s. The protective association with depressive symptoms was found for women using combination estrogen/progesterone formulations as well as among users of progestin-only contraceptives.
These results could have arisen because hormonal contraception reduces or stabilizes levels of depressive symptoms, but they should be interpreted in the context of evidence that women with depressive symptoms are less likely to start and adhere to hormonal contraception regimens. Almost one-third of women who begin using hormonal contraceptives discontinue use within 1 year. Previous clinical research has documented that women with a history of depression are less likely to choose exogenous hormone use as a contraception method and are more likely to discontinue use even if they begin using hormonal contraceptives. Further, women who perceive a negative mood effect of hormonal contraceptives are more likely to discontinue use. Women who discontinue use of oral contraceptives because of side effects are less likely to restart. Thus, hormonal contraceptive users at any time point may be overselected for less depression than nonusers of hormonal contraceptives. Indeed, odds ratios were in the direction of women with high depression scores being less likely to subsequently use hormonal contraception (Figure 3). However, controlling for past depressive symptoms, the protective association of hormonal contraceptives with depressive symptoms and suicide attempts remained robust. Nevertheless, the associations presented here are likely to at least partially reflect a nonadherence effect related to depressed mood. This underscores the importance of identification and treatment of women with depression in order to promote health in other domains, such as reproductive health and medication adherence.
Existing literature on hormonal contraception and depression has been primarily confined to small, unrepresentative samples. Among these smaller studies, few cohesive findings have emerged. Daily diary studies have produced conflicting results, with some finding no mood differences across the cycle when comparing users with nonusers and some finding improvement in mood, as well as clinically significant positive affect and sexual desire, and others finding heightened negative mood and negative reaction to stressors. A consistent finding in the literature is that there is less variation in mood among women taking hormonal contraceptives (reviewed by Oinonen and Mazmanian), which corresponds to clinical research showing that women who experience severe mood problems during the menstrual cycle (e.g., premenstrual dysphoric disorder) demonstrate improvement on hormonal contraceptives due to a more stable mood across the cycle. In that context, our findings show strong and robust associations, with hormonal contraceptive users being at substantially reduced risk for depressed mood in one of the largest population-based studies to have examined this issue in the literature.
Estrogen has widespread effects on the brain and behavior through direct and indirect genomic and nongenomic actions (see McEwen et al. for a detailed review). Estrogen receptors have been found in the hypothalamus, amygdala, hippocampus, and prefrontal cortex and in autonomic centers of the brain stem. In these regions, estrogen receptors are detectable in neuronal cell bodies, dendrites, presynaptic terminals, mitochondria, and glial cells. Through these receptors, estrogens modulate neuroplastic processes as well the activity of the major neurotransmitter and neuromodulator systems, including the cholinergic, noradrenergic, serotonergic, dopaminergic, glutamatergic, neuropeptide Y, and opioidergic systems, as well as brain-derived neurotrophic factor and second messenger pathways—all of which have been implicated in the pathophysiology of mood disorders. Through such mechanisms, estrogen may exert mood-regulating effects in oral contraceptive users. In addition, through its effects on the hippocampus and hypothalamus, estrogen modulates the activity and reactivity of the hypothalamic-pituitary-adrenal axis, which in turn is implicated in the pathophysiology of depression and mood regulation. Further, exogenous estrogen can affect cortisol responses and hypothalamic-pituitary-adrenal activity, which are both implicated in the regulation of mood. For example, Kirschbaum et al. documented that free salivary cortisol responses to a laboratory-generated psychosocial stressor were lowest among hormonal contraceptive users as compared with men as well as women in the luteal and follicular phases, while total cortisol responses did not differ between groups, suggesting a higher level of cortisol-binding globulin in the hormonal contraceptive users. Recent evidence also indicates substantially increased cortisol-binding globulin among hormonal contraceptive users compared with noncompliant users. By binding free cortisol, cortisol-binding globulin inactivates the hormone's effects, leading to a reduced biologically active portion of circulating cortisol. A reduction of bioactive cortisol in hormonal contraceptive users could potentially be neuroprotective under conditions of chronic stress, thereby reducing depression risk.
Little research has examined the role of exogenous hormone use in suicidality, and existing research has focused on mortality from suicide rather than suicide attempts. Hannaford et al. documented a suggestive increase in the risk of suicide mortality among oral contraceptive users, although mortality could occur long after use rather than concurrently, and results are not consistent with those of other large cohort studies. Risk factors for attempted suicide differ substantially from risk factors for completed suicide; thus, different associations with hormonal contraceptive use are likely. Emerging evidence suggests that women in the late luteal phase of the menstrual cycle may be at heightened risk for suicide attempts and severe suicide attempts; thus, hormonal contraceptive use may prove to be a useful adjunct in stabilizing mood among women with suicidal ideation.
Several limitations of this study are notable. While we were able to control for a wide range of factors associated with the decision to use hormonal contraceptives, residual confounding as an explanation for these results cannot be ruled out because of the study's observational design. The decision to use a particular type of contraception is not randomly distributed; women in stable partnerships may choose a method with more stability, such as sterilization, an IUD, or a hormonal method, although available data indicate that barrier protection remains a popular choice among women in stable partnerships. In this sample, women in monogamous relationships chose barrier protection less frequently than hormonal contraception. Thus, relationship factors such as partnership stability and overall health-care utilization may be related to both hormonal contraceptive decisions and levels of depressive symptoms. These differences underscore our analytical plan to examine different groups of contraceptive users; among users of highly effective methods (e.g., sterilization, IUD), we found no association with depressive symptoms or suicide attempts, suggesting that partnership stability does not explain the relationships observed here. Further, we also controlled for a monogamous partnership in the past year. Nevertheless, continued research in study samples with comprehensive information on the stability and satisfaction of sexual partnerships would enhance our ability to make causal inferences about these associations.
Further, we did not have information on the hormonal contraceptive formulations used by women in this study. Estrogen and progestin doses vary by formulation, and such information would be helpful in establishing the specificity of this association, as well as potential dose-response. We also did not have information on whether IUDs contained hormones. However, assuming that these users would be expected to have lower levels of depressive symptoms, this potential misclassification would bias the users of highly effective contraceptives towards lower levels of depressive symptoms than we report. Data on synthetic estrogen and progestin dose are also critical as a next step in this research, so that a potential dose-response or threshold can be established.
Finally, our results are generalizable only to sexually active women, because questions regarding contraceptive use were asked in the context of current partnerships. Women who are not in sexual relationships may be using hormonal contraception for a variety of reasons.
In summary, these results, notwithstanding limitations of study design and measurement, warrant further investigation of the potentially protective effects of hormonal contraceptives on mood in epidemiologic studies. Depression remains one of the most disabling health conditions worldwide, and it disproportionately affects women. Given the widespread prevalence of hormonal contraceptive use among young women in the United States and worldwide, systematic investigation of the role of exogenous hormones (including potential dose-response relationships) in regulating mood, as well as the role of mood in predicting nonadherence to hormonal contraceptive regimens, is warranted.
Discussion
In the present study, we found a protective association between hormonal contraceptive use and depressive symptoms, as well as suicide attempts, in a population-based sample of young, sexually active US women. These associations persisted even after controlling for all measured factors related to health and lifestyle, including prior depressive symptoms and hormonal contraceptive use. The study documented this effect among these women at 2 different life stages, once in the early 20s and once in the late 20s/early 30s. The protective association with depressive symptoms was found for women using combination estrogen/progesterone formulations as well as among users of progestin-only contraceptives.
These results could have arisen because hormonal contraception reduces or stabilizes levels of depressive symptoms, but they should be interpreted in the context of evidence that women with depressive symptoms are less likely to start and adhere to hormonal contraception regimens. Almost one-third of women who begin using hormonal contraceptives discontinue use within 1 year. Previous clinical research has documented that women with a history of depression are less likely to choose exogenous hormone use as a contraception method and are more likely to discontinue use even if they begin using hormonal contraceptives. Further, women who perceive a negative mood effect of hormonal contraceptives are more likely to discontinue use. Women who discontinue use of oral contraceptives because of side effects are less likely to restart. Thus, hormonal contraceptive users at any time point may be overselected for less depression than nonusers of hormonal contraceptives. Indeed, odds ratios were in the direction of women with high depression scores being less likely to subsequently use hormonal contraception (Figure 3). However, controlling for past depressive symptoms, the protective association of hormonal contraceptives with depressive symptoms and suicide attempts remained robust. Nevertheless, the associations presented here are likely to at least partially reflect a nonadherence effect related to depressed mood. This underscores the importance of identification and treatment of women with depression in order to promote health in other domains, such as reproductive health and medication adherence.
Existing literature on hormonal contraception and depression has been primarily confined to small, unrepresentative samples. Among these smaller studies, few cohesive findings have emerged. Daily diary studies have produced conflicting results, with some finding no mood differences across the cycle when comparing users with nonusers and some finding improvement in mood, as well as clinically significant positive affect and sexual desire, and others finding heightened negative mood and negative reaction to stressors. A consistent finding in the literature is that there is less variation in mood among women taking hormonal contraceptives (reviewed by Oinonen and Mazmanian), which corresponds to clinical research showing that women who experience severe mood problems during the menstrual cycle (e.g., premenstrual dysphoric disorder) demonstrate improvement on hormonal contraceptives due to a more stable mood across the cycle. In that context, our findings show strong and robust associations, with hormonal contraceptive users being at substantially reduced risk for depressed mood in one of the largest population-based studies to have examined this issue in the literature.
Estrogen has widespread effects on the brain and behavior through direct and indirect genomic and nongenomic actions (see McEwen et al. for a detailed review). Estrogen receptors have been found in the hypothalamus, amygdala, hippocampus, and prefrontal cortex and in autonomic centers of the brain stem. In these regions, estrogen receptors are detectable in neuronal cell bodies, dendrites, presynaptic terminals, mitochondria, and glial cells. Through these receptors, estrogens modulate neuroplastic processes as well the activity of the major neurotransmitter and neuromodulator systems, including the cholinergic, noradrenergic, serotonergic, dopaminergic, glutamatergic, neuropeptide Y, and opioidergic systems, as well as brain-derived neurotrophic factor and second messenger pathways—all of which have been implicated in the pathophysiology of mood disorders. Through such mechanisms, estrogen may exert mood-regulating effects in oral contraceptive users. In addition, through its effects on the hippocampus and hypothalamus, estrogen modulates the activity and reactivity of the hypothalamic-pituitary-adrenal axis, which in turn is implicated in the pathophysiology of depression and mood regulation. Further, exogenous estrogen can affect cortisol responses and hypothalamic-pituitary-adrenal activity, which are both implicated in the regulation of mood. For example, Kirschbaum et al. documented that free salivary cortisol responses to a laboratory-generated psychosocial stressor were lowest among hormonal contraceptive users as compared with men as well as women in the luteal and follicular phases, while total cortisol responses did not differ between groups, suggesting a higher level of cortisol-binding globulin in the hormonal contraceptive users. Recent evidence also indicates substantially increased cortisol-binding globulin among hormonal contraceptive users compared with noncompliant users. By binding free cortisol, cortisol-binding globulin inactivates the hormone's effects, leading to a reduced biologically active portion of circulating cortisol. A reduction of bioactive cortisol in hormonal contraceptive users could potentially be neuroprotective under conditions of chronic stress, thereby reducing depression risk.
Little research has examined the role of exogenous hormone use in suicidality, and existing research has focused on mortality from suicide rather than suicide attempts. Hannaford et al. documented a suggestive increase in the risk of suicide mortality among oral contraceptive users, although mortality could occur long after use rather than concurrently, and results are not consistent with those of other large cohort studies. Risk factors for attempted suicide differ substantially from risk factors for completed suicide; thus, different associations with hormonal contraceptive use are likely. Emerging evidence suggests that women in the late luteal phase of the menstrual cycle may be at heightened risk for suicide attempts and severe suicide attempts; thus, hormonal contraceptive use may prove to be a useful adjunct in stabilizing mood among women with suicidal ideation.
Several limitations of this study are notable. While we were able to control for a wide range of factors associated with the decision to use hormonal contraceptives, residual confounding as an explanation for these results cannot be ruled out because of the study's observational design. The decision to use a particular type of contraception is not randomly distributed; women in stable partnerships may choose a method with more stability, such as sterilization, an IUD, or a hormonal method, although available data indicate that barrier protection remains a popular choice among women in stable partnerships. In this sample, women in monogamous relationships chose barrier protection less frequently than hormonal contraception. Thus, relationship factors such as partnership stability and overall health-care utilization may be related to both hormonal contraceptive decisions and levels of depressive symptoms. These differences underscore our analytical plan to examine different groups of contraceptive users; among users of highly effective methods (e.g., sterilization, IUD), we found no association with depressive symptoms or suicide attempts, suggesting that partnership stability does not explain the relationships observed here. Further, we also controlled for a monogamous partnership in the past year. Nevertheless, continued research in study samples with comprehensive information on the stability and satisfaction of sexual partnerships would enhance our ability to make causal inferences about these associations.
Further, we did not have information on the hormonal contraceptive formulations used by women in this study. Estrogen and progestin doses vary by formulation, and such information would be helpful in establishing the specificity of this association, as well as potential dose-response. We also did not have information on whether IUDs contained hormones. However, assuming that these users would be expected to have lower levels of depressive symptoms, this potential misclassification would bias the users of highly effective contraceptives towards lower levels of depressive symptoms than we report. Data on synthetic estrogen and progestin dose are also critical as a next step in this research, so that a potential dose-response or threshold can be established.
Finally, our results are generalizable only to sexually active women, because questions regarding contraceptive use were asked in the context of current partnerships. Women who are not in sexual relationships may be using hormonal contraception for a variety of reasons.
In summary, these results, notwithstanding limitations of study design and measurement, warrant further investigation of the potentially protective effects of hormonal contraceptives on mood in epidemiologic studies. Depression remains one of the most disabling health conditions worldwide, and it disproportionately affects women. Given the widespread prevalence of hormonal contraceptive use among young women in the United States and worldwide, systematic investigation of the role of exogenous hormones (including potential dose-response relationships) in regulating mood, as well as the role of mood in predicting nonadherence to hormonal contraceptive regimens, is warranted.
