Hormonal Coil Dosage and Its Impact on Depression Risk

The landmark approval of the first hormonal contraceptive (HC) in 1960 marked a significant milestone in women’s health, granting them unprecedented autonomy over their reproductive choices and enabling them to have greater control over the direction of their lives. Today, access to contraceptive methods is widely recognized as a fundamental human right, as emphasized by the World Health Organisation in 2014.

Currently, an estimated 40% of women of reproductive age are using hormonal contraceptives (HCs) (Kristensen, 2021). However, many choose to discontinue their use, often due to perceived psychological side effects (Martell, 2023). The existing epidemiological research exploring the connection between HCs and mood changes or depression has produced mixed results. While some studies suggest a protective effect of HCs on mood, particularly in certain populations, such as those suffering from premenstrual dysphoric disorder (PMDD) (Robakis, 2019), others indicate a negative correlation or no significant findings regarding HCs and depressive symptoms (Skovlund, 2016; Worly, 2018). These conflicting results may stem from variations across studies, highlighting the need for further research to clarify this relationship and consider the diverse effects of different hormone formulations and delivery methods (e.g., long-acting versus oral methods) across various populations.

This blog post delves into findings from a recent study conducted in Denmark (Larsen et al, 2024), which assessed the risk of depression among new users of three different doses of the levonorgestrel-releasing intrauterine system (LNG-IUS). This investigation is crucial not only for providing comprehensive counseling to potential users but also for promoting equitable access to contraception by addressing and alleviating concerns regarding possible side effects.

Understanding the Research Methodology

This prospective study utilized data from the Danish national health registry, focusing on a well-defined sample of women residing in Denmark who met specific criteria:

• Born in 1978 or later,
• Initiated use of an LNG-IUS between the ages of 15 and 44, and
• No prior diagnosis of a mental health disorder.

To determine incident cases of depression, the research team analyzed diagnostic records and prescriptions for antidepressants issued within 12 months following the insertion of the LNG-IUS. The risk of developing depression was calculated using Cox regression, adjusted for various known and measured confounding factors, such as age, educational background, family history of mental health issues, postpartum use of the IUS, and any medical disorders for which a high-dose IUS might be indicated.

Key Findings on Depression Risks Associated with LNG-IUS

The study analyzed data from 149,200 new LNG-IUS users, categorized as follows: 14.8% used a low-dose device, 32% used a medium-dose device, and 53.3% utilized a high-dose device. Users of high-dose IUS were generally older, had a history of childbirth, and were more likely to have been diagnosed with specific medical indications necessitating the use of an LNG-IUS, such as heavy menstrual bleeding, dysmenorrhea, endometriosis, or uterine fibroids.

In total, 2,258 cases of depression were identified, based on both diagnoses and antidepressant prescriptions. After 12 months, the prevalence of depression among low, medium, and high dose LNG-IUS users was recorded at 1.21%, 1.46%, and 1.84%, respectively. This indicates that 0.26% more individuals in the medium-dose group experienced depression compared to the low-dose group, while 0.63% more individuals in the high-dose group reported depression compared to the low-dose group; these differences represent relatively modest risks.

Of the identified cases, the majority were noted through prescriptions for antidepressants (n=2,110), with 366 women receiving formal diagnoses. To mitigate potential bias from including women who received antidepressants for reasons other than depression (e.g., anxiety disorders or chronic pain), the analysis was repeated focusing solely on those for whom depression was specifically indicated (n=1,198). In this refined analysis, the absolute risks were found to be 0.59% (low dose), 0.70% (medium dose), and 1.02% (high dose).

While the risk differences between low–medium and low–high doses were minor, a clear dose–response pattern emerged, indicating an increasing risk of depression correlating with higher doses of levonorgestrel, regardless of the method used to identify depression cases.

Notably, the heightened risk of depression in the high-dose LNG-IUS group compared to the low-dose group was consistent even after conducting several robustness checks. For instance, the authors performed separate analyses on specific subgroups, including nulliparous women (those with no history of childbirth), women under 30, and those who began using an LNG-IUS post-2017 (to account for variations in prescription patterns over time). Employing propensity score weighting, a technique designed to simulate randomization of baseline characteristics, the authors reaffirmed the existence of a dose–response relationship between levonorgestrel dosage and depression risk.

In another analysis involving women with a prior mental health disorder diagnosis (48,937 women), the risks associated with low, medium, and high-dose LNG-IUS users were observed to be 4.80%, 5.22%, and 5.91%, respectively. Interestingly, the difference in the proportion of high compared to low-dose LNG-IUS users who developed depression (1.11%) was notably larger than in the cohort without prior mental health diagnoses, suggesting that this group may exhibit increased sensitivity to higher LNG doses.

Interpreting the Study’s Conclusions on Depression Risk

The authors concluded that their research provides compelling evidence of a dose-dependent relationship between exposure to LNG and the subsequent risk of depression across the three different dosages of the intrauterine system. This association remained consistent even after accounting for potential confounding factors, including menstrual bleeding indications that often necessitate high-dose LNG-IUS use.

Importantly, a series of additional robustness checks were performed to address potential biases, and the observed dose-dependent relationship held steady across various analysis parameters. However, it is crucial to recognize that the risk differences (ranging from 0.27% to 0.66%) between low and medium to high LNG doses were relatively modest. This small increase in depression risk must be weighed against the potential beneficial effects of the LNG-IUS. Clinicians should therefore remain aware that while higher LNG-IUS doses may slightly elevate the risk of depression, the decision regarding LNG dosage should be made holistically, taking into account comorbid conditions and individual patient preferences.

Evaluating the Strengths and Limitations of the Study

The Nordic countries are well-known for their high-quality contributions to epidemiological research, largely due to their population-based registries that offer routinely collected, nearly complete prospective data (Laugesen et al., 2021). This Danish study exemplifies such research, benefiting from a large sample size representative of the national population. Consequently, it achieves a high level of statistical power, resulting in precise estimates and significantly reducing the chances of selection bias. Additionally, these registries possess a high positive predictive value for depression, meaning that individuals flagged as having depression are likely to be correctly identified, thereby minimizing “false positives.”

The study effectively addressed potential confounding factors related to gynecological conditions, particularly those commonly treated with high-dose LNG-IUS, postpartum initiation, and prior mental health disorders. Various sources of bias were controlled through rigorous sensitivity analyses, each of which maintained a consistent dose-dependent pattern for depression risk in relation to increasing levonorgestrel doses.

Nevertheless, certain limitations must be acknowledged. As noted by Soares (2024) in an editorial response, the exclusion of women who were not LNG-IUS users means that the absolute risks of depression are not contextualized within the broader general population. The annual incidence rate of depression among Danish women is approximately 1.3% (Musliner et al., 2019); thus, low to medium dose LNG-IUS users may not experience a significantly higher risk than what would typically be expected in the general population. This consideration is vital when interpreting the study’s results.

It is plausible that this study may have underestimated the actual risk of developing incident depression, as depression diagnoses were sourced only from the Psychiatric Central Register, which does not capture data from primary care settings. Consequently, a subset of patients experiencing mild depressive symptoms may have received lifestyle-focused counseling rather than medical treatment. Furthermore, there may be unknown factors related to women who previously experienced mild adverse reactions to other hormonal contraceptives, which could lead to their switch to LNG-IUS despite existing sensitivities to exogenous hormones.

Finally, while the differences among the three dosing groups were adjusted for in the analyses, there remains a possibility that other unknown or unmeasured variables may have influenced the outcomes.

Practical Implications for Healthcare Providers

Providing contraceptive counseling is a complex task that requires healthcare professionals to carefully evaluate the risks and benefits associated with various hormonal and non-hormonal options. Each individual’s unique medical history, lifestyle choices, past experiences with contraceptives, and personal preferences must be taken into account. The intricate relationship between hormonal contraceptives and mental health is not yet fully understood, as research yields mixed findings regarding protective effects, increased risks, or neutral outcomes across different contraceptives.

The findings of Larsen et al. (2024) offer novel insights into the relationship between increasing doses of LNG-IUS and the risk of developing depression. Given the dose–response pattern observed and corroborated by preclinical evidence regarding the effects of levonorgestrel on relevant biological pathways in both central and peripheral nervous systems, it is conceivable that levonorgestrel could modestly elevate depression risk. However, it is essential to note that due to the observational nature of this study, causal relationships cannot be definitively established.

Moreover, it is important to highlight that the absolute risk of depression was only marginally higher than the rates expected in the general population. For women using high-dose LNG-IUS, approximately one in every 152 may develop clinical depression within 12 months after starting the treatment, which is comparable to the risks observed in low dose users or the general population. This could be interpreted as a relatively small risk overall.

Simultaneously, healthcare providers must remain cognizant of this small risk. It has traditionally been thought that the LNG-IUS exerts its effects solely within the intrauterine environment, with minimal impact on broader physiological processes, including those in the central nervous system. However, the identified dose–dependent pattern in this research suggests that exogenous hormones released by the LNG-IUS may indeed influence depression risk, potentially through neuroendocrine pathways, including the modulation of hypothalamic-pituitary-adrenal (HPA) axis reactivity (Aleknaviciute et al., 2017). Providers should validate patient concerns regarding the anticipated mental health effects of the LNG-IUS and consider monitoring for depressive symptoms, particularly in patients with a history of psychiatric conditions or previous sensitivities to hormonal contraceptives.

Furthermore, the study focused on depression diagnoses and antidepressant prescriptions, which likely correspond to women experiencing more severe depressive symptoms. However, it is essential to recognize that some women could experience milder depressive symptoms that still significantly affect their quality of life. Consequently, the relatively minor risk of depression estimated by this study should not invalidate patients’ concerns. Future research is necessary to explore the effects of LNG-IUS on a broader spectrum of mental health symptoms across varying severities.

Author’s Statement of Interests

I am currently supervising a DPhil student who is investigating the impact of postpartum LNG-IUS use on breastfeeding rates.

Essential Links for Further Reading

Primary Research Article

Larsen SV, Mikkelsen AP, Ozenne B, et al. Association Between Intrauterine System Hormone Dosage and Depression Risk. American Journal of Psychiatry 2024; 181(9): 834–841. https://psychiatryonline.org/doi/full/10.1176/appi.ajp.20230909.

Additional References for Context

World Health Organisation (WHO). Ensuring human rights in the provision of contraceptive information and services: Guidance and recommendations. 2014. Geneva, Switzerland: Department of Reproductive Health and Research.
https://iris.who.int/bitstream/handle/10665/102539/9789241506748_eng.pdf;sequence=1

Kristensen SI, Lidegaard Ø. Hormonal contraceptive use in Denmark 2010-2019. Dan Med J. 2021; 68(6).
https://content.ugeskriftet.dk/sites/default/files/scientific_article_files/2021-05/a08200599_web.pdf

Martell S, Marini C, Kondas CA et al. Psychological side effects of hormonal contraception: a disconnect between patients and providers. Contracept Reprod Med. 2023; 8(9). https://doi.org/10.1186/s40834-022-00204-w

Robakis T, Williams KE, Nutkiewicz L. et al. Hormonal Contraceptives and Mood: Review of the Literature and Implications for Future Research. Curr Psychiatry Rep 2019;21(57). https://doi.org/10.1007/s11920-019-1034-z

Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø. Association of Hormonal Contraception with Depression. JAMA Psychiatry. 2016;73(11):1154–1162. doi:10.1001/jamapsychiatry.2016.2387

Worly BL, Gur TL, Schaffir J. The relationship between progestin hormonal contraception and depression: a systematic review. Contraception. 2018;97(6):478–489.
https://www.sciencedirect.com/science/article/pii/S0010782418300325?casa_token=wS982ncxPCUAAAAA:y-UQcrwyQHRkj81OYeLNcHr-B8581rp58G5XERqbb1kWrxwB9_1