Managing the risks of mood symptoms with LNG-IUS: a clinical perspective

Abstract

Introduction: Lack of awareness of reproductive hormone-related mood changes in the general population or limited acknowledgement of their existence by health care providers regularly contribute to fears or misconceptions about the link between hormonal contraception and potential mood changes. Recent media discussion linked the levonorgestrel intrauterine system (LNG-IUS 20 µg/d) to elevated cortisol levels and the possibility of panic attacks, anxiety, mood changes, sleep disturbance and restlessness. Efficacy of the LNG-IUS is based primarily on local effects but systemic effects, including a potential increase in mood symptoms, are a known risk and reflected in the product labelling for all LNG-IUS products.

Objective: There is a need to improve communication to the public and health care providers around potential risk of mood disorders in order to facilitate ‘informed choice’ amongst women considering an LNG-IUS as their contraceptive method and directly address the fears of women currently using an LNG-IUS.

Results: We propose a simple and brief, step-by-step process that can be embedded within current counselling that explores and clarifies the potential risk of developing mood symptoms prior to placement of LNG-IUS. It also addresses concerns from women using an LNG-IUS who either present with mood symptoms or are concerned about potential onset.

Conclusion: Mood symptoms with use of LNG-IUS are uncommon; however, all women, including those who may experience an increased sensitivity to certain progestins, should be counselled appropriately to raise awareness of the potential risk within an informed discussion around effectiveness, benefits and possible adverse events.

摘要：

简介：普通人群或卫生保健工作者对生殖激素相关的情绪变化认识有限, 这些常常导致人们对激素避孕方法及其潜在情绪变化之间的关系产生恐惧或误解。最近媒体的讨论将左炔诺孕酮宫内节育系统(LNG-IUS 20 ug/d)与皮质醇水平升高, 以及引起恐慌症、焦虑、情绪变化、睡眠障碍和焦躁不安的可能性联系起来。LNG-IUS的疗效主要基于局部作用, 而不是全身, 包括增加情绪症状的潜在风险, 这是一种已知的风险, 并在所有LNG-IUS产品的说明书上已注明。

目的：为了帮助那些正在考虑将LNG-IUS作为避孕方法的女性进行“知情选择”, 并彻底解决目前正在应用LNG-IUS女性的恐惧, 有必要加强公众和卫生保健工作者之间关于LNG-IUS引起情绪障碍潜在风险的沟通。

结果:我们提出了一个简单扼要、循序渐进的过程, 可以嵌入到当前的咨询中, 在放置LNG-IUS之前就阐明出现情绪症状的潜在风险。它还解决了用LNG-IUS的女性的担忧, 这些人要么表现出情绪症状, 要么正在担心潜在的发病。

结论:放置LNG-IUS后出现情绪症状较少见;然而, 包括那些可能对某些孕激素敏感性增加的所有妇女, 都应该得到适当的咨询, 在进行有效性、益处和可能的不良反应的知情讨论中提高对潜在风险的认识。

Keywords:

• Mood symptoms
• LNG-IUS
• counselling
• progestins

Introduction

Changes in endogenous hormone levels throughout a woman’s life may impact psychological health; evidence suggests that some women might be particularly susceptible to developing mood symptoms (new onset or recurrent) [1], during ‘windows of vulnerability’ while experiencing significant hormone fluctuations [1]. Such ‘windows’ would contribute to the prevalence of premenstrual symptoms (PMS), premenstrual dysphoric disorder (PMDD), postpartum depression and depression during the menopause transition [1–5]. Hormones and neurotransmitters share common pathways and receptor sites in the areas of the brain linked to mood. Hormone receptors are found in areas of the brain involved in the processing of emotions, such as the limbic system (including the amygdala) and the prefrontal cortices [1,6,7]. Lack of awareness of these reproductive hormone-related mood changes in the general population or limited acknowledgement of their existence by health care providers regularly contribute to fears or misconceptions about the link between hormonal contraception and potential mood changes. Most recently, media discussion focussed on a study by Aleknavicuite et al. [8] linking the levonorgestrel intrauterine system (LNG-IUS 20 µg/d) to elevated cortisol levels and the possibility of panic attacks, anxiety, mood changes, sleep disturbance and restlessness. Prior to this, media activity and an internet-based petition highlighted two key issues: first, that women choosing the LNG-IUS were mostly unaware of the potential for the development of mood symptoms as the nuances of hormone sensitivity were not communicated routinely by family doctors. Second, some women believed their fears about such effects were being dismissed as groundless. The petition was addressed to the German Medicines Committee and the Federal Institute for Drugs and Medical Devices and led to the initiation of a signalling procedure (Pharmacovigilance Risk Assessment Committee [PRAC]) by the European Medicines Agency (EMA). Following the announcement, the European Society of Contraception (ESC) issued an expert statement [9] on mood effects of the natural cycle and progestogen-only contraceptives (including LNG-IUS) and also discussed the link between cortisol levels, mood symptoms and the LNG-IUS 20 µg/d raised by Aleknavicuite et al. [8] The statement reiterated the ESC guidance for balanced and individualised counselling to identify those women who are more vulnerable to negative moods when using hormonal contraception [9].

In October 2017, as the responding authority for the EMA, the German authorities announced there was no new safety signal regarding mood symptoms and LNG-IUS, other than the already labelled effects on mood (depressed mood/depression) in the product prescribing information. [10] However, there was an opportunity to improve communication with the public and health care providers around this potential risk in two key areas: one that facilitates ‘informed choice’ amongst women considering an LNG-IUS as their contraceptive method and, at the same time, directly addresses the fears of women currently using an LNG-IUS. Health care providers need to know how to counsel women effectively to avoid unnecessary removal of an LNG-IUS and subsequent risk of unintended pregnancy, as well as any unnecessary, additional cost resulting from this procedure for women in some health care settings. With that in mind, clinicians with expert knowledge in both gynaecology and psychiatry met to discuss implications of the PRAC decision for clinical practice and expand upon ESC recommendations. Firstly, to support HCPs in increasing women’s awareness of the potential for both positive and negative effects on mood when using hormonal contraception and, secondly, to help improve the identification and counselling of those women with a history of reproductive-related mood symptoms i.e., those who have experience of mood symptoms associated with endogenous hormone fluctuations. These women should consider the potential risk of progestogen-related mood symptoms when opting for hormonal contraception, including the LNG-IUS; they should also consider the emergence of mood symptoms with an existing LNG-IUS.

Risk of mood symptoms and hormonal contraception

Despite robust evidence of mood-related symptoms associated with endogenous hormone changes, the association between the use of hormonal contraception and mood disturbances is considered more controversial due to inconsistent reports [11,12]. Whilst some prospective and retrospective studies suggest that between 4 and 17% of women using combined hormonal contraception (CHC) report increased anxiety and depressed mood. [13–15]. others suggest that CHC may reduce variability in mood across the menstrual cycle [16] or ameliorate the severity of symptoms [17]. Data from the Danish nationwide cohort study reported by Skovlund et al., [18,19] suggest that depression is a particular problem for younger women. A recent systematic review by Schaffir et al. [12] looked at publications focussed on the use of CHC and effects on mood over a 30-year period. The authors found no significant effect (beneficial or not) with CHC for most women but noted that less androgenic progestins exerted fewer effects on mood [12]. The review also reported that women with underlying mood disorders might have a predisposition to mood effects with CHC [12]. This conclusion was supported by the findings of a recent study by Bengtsdotter et al. [20] The authors went further to suggest that women with no psychiatric history have little risk of developing mood symptoms with use of CHC [20].

Risk of mood symptoms with LNG-IUS

Efficacy of the LNG-IUS is based primarily on local effects but small amounts of LNG released from the device enter and are absorbed via the bloodstream [21–24]. Serum concentration is dependent on the LNG-IUS used. Apter et al. [25], report average LNG serum concentrations to be 74.3 ng/L, 114 ng/L and 218 ng/L for LNG-IUS 13.5 mg, LNG-IUS 19.5 mg and LNG-IUS 20 μg/24 h, respectively, over three years of use.

Systemic effects, including a potential increase in mood symptoms, are a known risk and reflected in the product labelling for all LNG-IUS products [21–24]. Published data quantifying the impact of LNG-IUS on mood symptoms are limited. Data from comparative studies show poorly defined ‘mood disorder’ to be a more frequent side effect or reason for discontinuation with LNG-IUS than non-hormonal comparators [26–29]. Accumulated data on LNG-IUS studies suggest the method is associated with a change in mood in up to 18% of women [29–31] and that discontinuation rates due to self-reported mood changes or symptoms range from 4.4% to 5.4% [27,30]. However, these data come from studies reporting the incidence of all side effects and discontinuation rates that were not designed to measure mood changes with a validated instrument. Toffol et al. [32] found that when a validated tool such as the Beck Depression Inventory (BDI) was used there was no significant association between LNG-IUS use and the emergence of mood symptoms when comparing both users and non-users of hormonal contraception. The most recent study, by Gemzell-Danielsson et al., [33] comparing three different LNG-IUS devices, found that changes in mood affected 0.2% of users. Furthermore, a study involving post-partum women conducted by Roberts and Hansen [34] showed a significant lowering of risk of depression with use of LNG-IUS. Importantly, recent studies indicate a lack of evidence that the use of an LNG-IUS is associated with onset or worsening of depression or diagnosed psychiatric illness [35,36].

These findings should be considered in the overall context that women are at greater risk of depression (approximate 2-fold increased risk compared to men [37–39], with roughly 15% of women experiencing depression at some point in their lifetime [40], and also providing reliable contraception to women remains a continual challenge. Women presenting with mood symptoms associated with reproductive events i.e., premenstrual, postpartum or menopausal transition may be particularly prone to experiencing depression, particularly due to a heightened sensitivity to intense hormonal fluctuations [1].

Delivering best practice when counselling about the risk of mood symptoms

Elements of counselling around the risk of mood symptoms with hormonal contraception have been shared by the ESC. [6,9] They provide guidance to health care providers in the counselling of women, so they can better understand and consider potential adverse effects on psychological or cardiovascular health with hormonal contraception in general. Using these as framework together with the recommendations of the PRAC, the authors propose a simple and brief, step-by-step process that could be embedded within current counselling. It aims to explore and clarify the potential risk of developing mood symptoms prior to method placement (Table 1) and also address concerns from women using an LNG-IUS who either present with mood symptoms or are concerned about potential onset (Table 2).

Table 1. Counselling women about the risk of mood symptoms with LNG-IUS to facilitate informed choice.

1. Clarify general risk of potential mood symptoms	It is uncommon to see mood changes with use of the LNG-IUS; however, some women have an increased sensitivity to certain hormones
2. Use the medical history to identify individual risk Using questions that identify elements of history that may put a woman at risk, in addition to a general, neutral question about medication use	Idiopathic sensitivity to hormones	History of psychological symptoms
	Increased risk due to established hormone sensitivity: • For example, have you had any notable reactions to hormonal fluctuations within the menstrual cycle or notable reaction to use of an oral contraceptive pill in the past? Then if needed: • Did you notice a change in mood, irritability, anxiety, sleep pattern? • Was the reaction severe? How long did it last? How was it resolved?	Increased risk due to previous episode of mood disorder or depressive symptoms, for example, • Have you ever experienced any previous depressive episodes or anxiety disorders? • Have you ever taken any medication for depression? • Have you ever been hospitalised with depression? • Have you ever seen a psychiatrist for depression?
3. Counsel according to either general or individual risk	No evidence of risk	Suggested wording for simple counselling of risks • For all women, there is a possibility of a change in mood with hormonal contraception; for some, it is positive, for others, it can be negative • If it does occur, it is most likely in the first few weeks of use but it is reversible • The change can be due to fluctuating levels of hormone but if it does not resolve after 6–12 weeks OR is bothersome and causing concern, please return
	Evidence of risk	Suggested additional wording where there is evidence of risk • Your history suggests that you may be more sensitive to hormone changes or prone to changes to in mood and may be more likely to experience such a change

Table 2. Counselling LNG-IUS users presenting with mood symptoms or concerns about developing mood symptoms.

Counsel a returning patient according to timing of symptom onset
Symptoms ≤6 weeks post-insertion	• Assess severity and impact on daily living   ^ If mild to moderate, explain that plasma hormone levels reach their peak at 6 weeks and suggest waiting a little longer (agree suitable time to return) to see if the symptoms resolve on their own ^ If severe, refer for psychiatric evaluation and discuss removal of LNG-IUS • If previous history – ask if symptoms are similar to what they’ve experienced before or different • Ask about any changes/life events that could be causing the symptoms • If patient requests removal: • Counsel on implications of removal, for example, contraceptive efficacy or changes in bleeding if used for heavy menstrual bleeding (discuss other treatment options) • Counsel on possibility of similar effect with other hormonal preparations • If patient still requests removal, counsel around contraceptive options accordingly
Symptoms within 6–12 weeks of insertion	• Assess severity and impact on daily living • If mild to moderate discuss strategies to manage symptoms (including removal of LNG-IUS) • If severe, refer for psychiatric evaluation and discuss removal of LNG-IUS • If previous history – ask if symptoms are similar to what they’ve experienced before or different • Ask about any changes/life events that could be causing the symptoms • If patient requests removal: • Counsel on implications of removal, for example, contraceptive efficacy or changes in bleeding if used for heavy menstrual bleeding (discuss other treatment options) • Counsel on possibility of similar effect with other hormonal preparations • If patient still requests removal, counsel around contraceptive options accordingly
Symptoms 12 months after insertion	• Counsel that reactions to the hormone in the LNG-IUS usually occur within the first three months [42,43] therefore her symptoms are unlikely to be related • Counsel as above if patient expresses continued concern or requests removal
Patient returns (at any time point) expressing concern about the likelihood of developing symptoms prompted by media stories	• Counsel that reactions to the hormone in the LNG-IUS usually occur within the first three months [42,43] and ask about timing of onset • If insertion <3 months, refer to patient history screening questions • If insertion >3 months ago, counsel that reactions to the hormone in the LNG-IUS usually occur within the first three months therefore if she has not developed any symptoms by now, she is unlikely to do so in the future • If patient requests removal: • Counsel on implications of removal, for example, contraceptive efficacy or changes in bleeding if used for heavy menstrual bleeding (discuss other treatment options) • Counsel on possibility of similar effect with other hormonal preparations • If patient still requests removal, counsel around contraceptive options accordingly

Counselling women about the risk of mood symptoms with LNG-IUS to facilitate informed choice

Clarification/statement of risk of mood symptoms

Counsel women regarding the low risk of mood symptoms with LNG-IUS and raise awareness of the fact that some women may have a greater sensitivity to hormones.

Taking a history to establish individual risk

Ask simple, neutral questions to establish any history of psychological symptoms, including post-partum depression, PMS, PMDD and CHC use and previous sensitivity to progestins (including LNG), during a routine medical history. Asking about previous medication use or hospitalisation for depression provides insights into psychological history.

Counselling according to individualised risk

Where there is no evidence of a history of mood symptoms, advise women that LNG-IUS is generally well-tolerated but a small number of women experience changes in mood, some of which can be positive, for example, in PMDD [41]. Counsel women about this potential risk within a discussion about effectiveness, convenience, non-contraceptive benefits and possible adverse effects of LNG-IUS. Where there is evidence of sensitivity to hormonal fluctuations or a history of mood symptoms unrelated to the use of hormonal contraception, again discuss the potential risk, the likely timing of onset and duration, and provide reassurance around reversibility within a framework of informed choice. Women should be advised that changes in mood with hormonal contraception are most likely in the first few weeks but if they do not resolve after 6 to 12 weeks or are causing concern then they should return for advice.

If a woman chooses LNG-IUS, simple and widely used self-completion tools such as the Beck Depression Inventory (www.beckinstitute.org) can be used to establish a baseline score that can be reviewed at follow-up. Even without formal assessment, a simple question such as ‘Have you noticed any changes in your mood – either positive or negative – in the last three months (or relevant follow-up period)‘represents a simple, open approach to identifying the presence of symptoms at the 1-3-month post-placement follow-up visit. Asking about other contributing factors to psychosocial changes, for example, stressful life events could help identify other potential causes of mood change. However, the method should be recommended with caution for women with a history of severe mood symptoms or hormone-related mood disturbances.

Counselling LNG-IUS users presenting with mood symptoms or concerns about developing mood symptoms

Allaying concerns about the presence or likelihood of mood symptoms and use of LNG-IUS

Women may present with mood symptoms they believe to be related to the use of LNG-IUS or may be concerned about their potential risk of developing mood symptoms prompted by what they have heard or read in the media. Establishing a timeline for symptom onset (see Table 2), is useful when discussing a potential link between mood symptoms and LNG-IUS. This approach can also be used to reassure women who present with concerns in the absence of new symptoms. Questions about severity of symptoms and relationship to previous history (if relevant) and changes or life events that may be affecting mood are also important. In all cases, the option of LNG-IUS removal should be discussed.

Conclusion

Mood symptoms with use of LNG-IUS are uncommon. Some women may experience an increased sensitivity to certain progestins but, currently, there is limited evidence to guide practitioners which women may be at greater risk than others. Therefore, it is important to raise awareness of the potential risk of mood symptoms with LNG-IUS as part of an informed discussion around effectiveness, benefits and possible adverse events. Counselling those women identified as being at greater risk according to established best practice is also important. Meanwhile, more research is needed to accurately quantify the absolute risk of mood symptoms with hormonal contraception. Some key questions regarding the risk of mood symptoms with LNG-IUS remain unanswered to some extent, namely: prevalence; time of symptom onset and duration; severity; predisposing factors that elevate risk and reversibility. In addition, insights into time of and response to removal where necessary; strategies for symptom management other than removal including treatment of underlying mood disorders (both pharmacological and psychological approaches) and potential benefits of early follow-up visits after placement are needed.

Acknowledgments

The authors received honoraria for attendance at one meeting where the concept of a publication was discussed but no honoraria were paid for contributions to this manuscript.

This publication and its content are solely the responsibility of the authors. Medical writing assistance was provided by Lynn Hamilton of Clark Health Communications under the direction of the authors and paid for by Bayer AG.

Disclosure statement

Johannes Bitzer has worked as an Advisor for and received honoraria from Bayer AG, Merck, Teva, Exeltis, Lilly, Boehringer-Ingelheim, Vifor and Gedeon Richter. He has also given invited lectures and received honoraria from Bayer AG, Merck, Johnson and Johnson, Teva, Mylan, Allergan, Abbott, Lilly, Pfizer and Gedeon Richter.

Claudio Soares reports the receipt of grants from Ontario Brain Institute and the Ontario Research Foundation. He has received support outside the submitted work from Pfizer, Sunovion, Merck and Lundbeck.

Andrea Rapkin has nothing to disclose.