Patients with adverse mood effects from combined oral contraceptives have lower levels of prepulse inhibition than healthy controls
Introduction
Among young women, combined oral contraceptive (COC) pills is the most common type of contraception with a user frequency in Sweden of almost 56% within the ages of 18–24 and 29% in ages 25–34 (Lewin et al., 1996). Ever since the introduction of COCs in the 1960s, one of the major reasons for discontinuing the use has been mood-related side effects, such as irritability, mood swings and depressive symptoms (Sanders et al., 2001; Oinonen and Mazmanian, 2002; Robinson et al., 2004). A recent prospective study reported that 7% of women on COC suffered from increased anxiety and 10% from depressive mood (Ernst et al., 2002). When assessed retrospectively, 16.3% of women reported oral contraceptive pill-related premenstrual mood deterioration (Joffe et al., 2003) and discontinuation rates due to adverse mood symptoms were of 14–21%, depending on age (Larsson et al., 1997). As many women refrain from using oral contraception because of adverse mood effects from COCs, it is important to elucidate the underlying pathophysiology for these changes in affect.
Despite the fact that COCs have been used for a long time and have been the subject of many studies, several issues related to adverse mood effects from COCs remain to be elucidated. These include the wide variety of progestin formulations used in COCs and the estrogenic or progestagenic profile of the preparation. Also, as subjects who had been prospectively defined as suffering from premenstrual syndrome (PMS) were more prone to report negative mood while on COCs (Cullberg, 1972), the prevalence of PMS or premenstrual dysphoric disorder (PMDD) prior to COC use could contribute to these adverse mood effects. Drospirenone is a spironolactone analog with antimineralocorticoid and antiandrogenic activities and drospirenone-containing COCs have been evaluated in several recent studies for treatment of PMDD with positive results (Freeman, 2002; Pearlstein et al., 2005). However, the possibility still remains that certain women with severe PMS, or subthreshold PMDD, are more likely to suffer from adverse mood effects during COC use than women with no cyclical mood changes. This might especially hold true for preparations containing levonorgestrel as these brands are more symptom provoking than COCs containing drospirenone (Sangthawan and Taneepanichskul, 2005).
The typical manifestation of PMDD is a recurrent constellation of physical and negative mood symptoms that emerge during the luteal phase and remit within a few days of the follicular phase (Halbreich et al., 2007). Symptoms are closely related to ovarian steroids as they occur only during ovulatory menstrual cycles (Hammarback and Backstrom, 1988; Hammarback et al., 1991; Sundstrom et al., 1999a) or during progesterone (Bjorn et al., 2003; Andreen et al., 2005) or estradiol administration (Schmidt et al., 1998). In addition to negative mood symptoms, objective manifestations of excitability, such as the acoustic startle response, are also affected in PMDD patients. The acoustic startle response is increased in an animal model of PMDD (Gulinello et al., 2003) and was recently also shown to be increased in PMDD patients (Epperson et al., 2007; Kask et al., 2007). The acoustic startle reflex (ASR) is a withdrawal reflex to sudden or noxious auditory stimuli which can be measured as an eyeblink in humans or as a whole-body response in laboratory animals (Davis, 1980). In addition, the acoustic startle response is also regulated by the agents thought to be critical to the etiology of premenstrual symptoms, notably progesterone fluctuations and underlying alterations in inhibitory neurotransmission via the GABAA receptor (Toufexis et al., 2004).
Sensorimotor gating can also be assessed by measuring prepulse inhibition (PPI) of the startle response using the PPI component of the ASR, which is thought to reflect an individual's ability to screen or “gate” sensory stimuli. The PPI paradigm uses a weak, non-startling acoustic stimulus (the prepulse) that typically decreases the reflexive eyeblink response (startle) produced by the subsequent startling target stimulus (the pulse). We have recently shown that women with PMDD have lower levels of PPI during the late luteal phase of the menstrual cycle compared to healthy controls (Kask et al., 2007). Ovarian steroids appear to influence PPI because women have lower levels of PPI than do men (Swerdlow et al., 1993) but only in the mid-luteal phase (Swerdlow et al., 1993; Jovanovic et al., 2004).
Given the similarities between premenstrual symptoms and adverse mood symptoms during COC use, the possibility of a similar underlying pathophysiology should be evaluated. As PMDD patients previously have been shown to have an increased acoustic startle response and deficient PPI, the primary aim of the current study was to compare startle response and PPI in patients with adverse mood effects of COCs and asymptomatic COC users. A secondary aim was to investigate startle response and PPI in former users of COCs, where discontinuation was, or was not, due to adverse mood effects.
Section snippets
Subjects
Two hundred and eighty-five women aged 19–38 with ongoing or past experience of COCs were screened for inclusion in the study. Patients were recruited from advertisement in newspapers and on advertising boards at Health Care Centers. Following a telephone screening, 117 women with different experiences of COCs were included in the study. Of these, 30 women were currently on COCs with no reports of adverse mood symptoms (COC-fine), 28 women were currently on COCs and experiencing mood-related
Results
Five subjects (one COC-fine, one COC-mood, one pCOC-fine and two subjects in the pCOC-mood group) were considered as non-responders. For technical reasons, the data from one COC-mood subject was lost. Hence, the study group consisted of 29 COC users without adverse mood symptoms (COC-fine), 26 COC users with adverse mood symptoms (COC-mood), 26 prior COC users without adverse mood symptoms (pCOC-fine), and 30 prior COC users with prior adverse mood symptoms (pCOC-mood). One patient in the
Discussion
The main finding of the present study was that patients with retrospective reports of adverse mood effects during ongoing treatment with combined oral contraceptives (COCs) displayed lower levels of prepulse inhibition (PPI) compared to asymptomatic COC users.
Our observation of lower levels of PPI in COC users with adverse mood symptoms correspond well with our prior study in PMDD patients, where PMDD patients displayed lower levels of PPI in the late luteal phase compared to healthy controls (
Role of funding source
This study was supported by grants from the Tore Nilsson Foundation, The Swedish Research Council project K2008-54X-20642-01-3, the Family Planning Foundation Uppsala, Magnus Bergwall Foundation and The Swedish Society of Medicine.
Conflict of interest
None of the authors have any conflicts to disclose.
Acknowledgments
Ulla Geifalk is acknowledged for her kind help with the steroid hormone analyses.
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