Since its introduction in 1950, the combined oral contraceptive pill has been used by countless women as a method for birth control (Liao P. Can Fam Physician. 2012 Dec; 58[12]:e757-e760).
Hormonal contraception (HC) provides women with both contraceptive and noncontraceptive benefits, most notably a method for avoiding unintended pregnancy. In addition to being an effective method of contraception, oral contraceptive pills (OCPs) are well established for treating conditions such as hirsutism, pain symptoms associated with endometriosis and adenomyosis, and pelvic inflammatory disease, among others (Schindler A. Int J Endocrinol Metab. 2013 Winter;11[1]:41-7).
IntimMedicine Specialists
Dr. James A. Simon
Combined hormonal contraceptives are also first-line treatment for women with menstrual disorders, and in women with polycystic ovary syndrome, can offer an effective long-term method to regulate their menstrual cycle, decrease androgens, clear up oily skin and acne, and reduce facial hair while also providing them with effective contraception (de Melo et al. Open Access J Contracept. 2017;8:13-23).
Associations between ‘the pill’ and mood effects remain controversial
More than 100 million women worldwide use hormonal contraceptives today, yet despite this, the data are mixed regarding the prevalence and extent of neuropsychiatric symptoms and mood changes associated with use of “the pill.” Some studies show combined oral contraceptives are associated with a decrease in general well-being, but had no effect on depression, in women compared with placebo (Zethraeus N et al. Fertil Steril. 2017 May;107[5]:1238-45).
However, a large Danish study published in JAMA Psychiatry of more than 1 million women found a significant association between use of hormonal contraception and antidepressant use or first diagnosis of depression, with adolescents having a higher rate of first depression diagnosis and antidepressant use compared with women 20–30 years old (Skovlund C et al. JAMA Psychiatry. 2016 Nov 1;73[11]:1154-62).
Studies have also shown long-term exposure to levonorgestrel is significantly associated with anxiety and sleep problems in women without a history of these issues (Slattery J et al. Drug Saf. 2018 Oct;41[10]:951-8). A recent small nationwide cohort study in France suggests this may also be true of levonorgestrel delivered by intrauterine devices (IUD) and the association may be dose-dependent (Roland N et al. JAMA. 2023;329[3]:257-9).
Of note, a study published in the American Journal of Psychiatry found a nearly twofold risk of suicide attempt and over threefold risk of suicide among women taking hormonal contraception compared with women who had never used hormonal contraceptives (Skovlund et al. Am J Psychiatry. 2017 Nov 17:appiajp201717060616).
Knowledge gaps make drawing conclusions difficult
The latest information on use of antidepressant and antianxiety medications in women of reproductive age (18-44 years) is sparse and, in some cases, outdated. According to data from the National Health and Nutrition Examination Survey, 18.6% of adult women 18 years or older reported using antidepressant medications within the last 30 days in 2017-2018, an increase from 13.8% in 2009-2010. Among women aged 15-44 year with private employer–sponsored insurance surveyed during 2008-2013, the results showed 15.4% of women filled a prescription for an antidepressant. We must look back further to find data on antianxiety medication use among women aged 18-44 years where use of antianxiety drugs (anxiolytics, sedatives, and hypnotics) was 4.3% between 2005 and 2008.
A lack of literature in this area is likely due to significant underreporting, and an inability to select patients who are sensitive to or at risk of developing neuropsychiatric symptoms resulting from hormonal contraception use because the true pathophysiology is unknown. Existing studies tend to use varying methods to assess mood changes, and do not usually specify hormonal contraceptive use type in their analyses (Schaffir J et al. Eur J Contracept Reprod Health Care. 2016 Oct;21[5]:347-55).
Studies of this nature also require large sample sizes, but the percentage of women who develop neuropsychiatric symptoms from hormonal contraceptive use has historically been relatively small. In the late 1990s, Rosenberg and colleagues found 46% of 1,657 women discontinued oral contraceptives due to side effects within 6 months of starting a new prescription; of these women, 5% reported mood changes as their reason for discontinuing oral contraceptives (Rosenberg M et al. Am J Obstet Gynecol. 1998 Sep;179[3 Pt 1]:577-82).
One might expect that, as lower dosage combined hormonal contraceptives were developed in the 1980s, that the rate of reporting psychological side effects would continue to decrease as well. Yet greater awareness of the potential for mood changes while on “the pill” as outlined by the lay press and social media may be leading to increased reporting of neuropsychiatric effects in women. In a recent cross-sectional survey of 188 women in New York, 43.6% said they experienced mood changes while on hormonal contraceptives, and 61.2% of women with histories of psychiatric illness reported mood changes they attributed to hormonal contraceptives (Martell S et al. Contracept Reprod Med. 2023;8:9).
Martell and colleagues found 48.3% of women cited side effects as a reason for discontinuing hormonal contraception, and 43 participants mentioned psychological side effects unprompted, including 2 patients with suicidal thoughts. The authors said this suggests “psychological side effects, at least in part, may have impacted” HC users’ decisions to switch from OCPs to an alternative method of contraception.
It is also not clear what risk factors exist for women who develop neuropsychiatric symptoms from hormonal contraceptive use. First, it is important to note that both progestin-only contraceptives and combined hormonal contraceptives are classified by the Centers for Disease Control and Prevention’s US Medical Eligibility Criteria for Contraceptive Use, 2016 as having no restrictions for use, including among patients with depression. While women in a smaller subgroup have significant neuropsychiatric symptoms related to their hormonal contraceptives, the underlying mechanism is unknown, and is thought to be largely related to the progestogen component of combined hormonal contraceptives or progestogen-only contraceptives (Mu E. Aust Prescr. 2022 Jun; 45[3]:75-9). We know that some women are hormone sensitive, while others are less so, and some not at all. Progestogens could affect mood as a direct action of the progestogen, because progestogens can be neurosteroids, or the progestogen effect could be mediated secondarily through a change in that woman’s own production of or bioavailability of androgens or naturally occurring estrogens (Giatti S. J Mol Endocrinol. 2016 Aug;57[2]:R109-26).
Here, we also find that currently available evidence limits our ability to draw firm conclusions. A study by Berry-Bibee and colleagues found a “low concern for clinically significant interactions” between hormonal contraception and psychotropic drugs, but was limited by quality/quantity of evidence (Berry-Bibee E et al. Contraception. 2016 Dec;94[6]:650-67). Interestingly, a study by Robinson and colleagues from the mid-2000s posited based on low evidence that “psychological response to the practice of contraception” was a potential explanation for the side effect profile of hormonal contraception (Robinson S et al. Med Hypotheses. 2004;63[2]:268-73).
Further, it may be that women with premenstrual dysphoric disorder (PMDD) might be selected for oral contraceptives, and they are predisposed to other neuropsychiatric problems. Estimates have placed the prevalence of comorbid psychiatric disorders such as anxiety, major depression, bipolar disorder, and posttraumatic stress disorder as high as 70% for women with PMDD (Sepede G et al. Neuropsychiatr Dis Treat. 2020;16:415-26). This phenomenon is not new, having been characterized in the lay literature nearly 20 years ago, by endocrinologist Geoffrey P. Redmond, MD (Redmond GP. The Hormonally Vulnerable Woman. New York: HarperCollins; 2005).
While the cause is not exactly idiosyncratic, They tend to have an entire spectrum of responses to the progestogens in combined or progestin-only contraceptives, ranging from just a flattened affect – which could easily be explained by their flattened level of endogenous hormones – to frank depression. Their frank depression, in turn, can be demonstrated to include suicidal ideation and actual suicide.
Compounding this issue is a woman’s perception of her sexuality. Some women with low sexual desire or sexual problems who are younger may have more distress about their problems compared with women of older reproductive age. While the reason for that is not clear, it may be that in the sexual arena, it is more important for some younger women to be a sexual person than in perimenopausal women, or that women who are younger are more likely to be partnered than women of older reproductive age. While the European Society of Sexual Medicine concluded in a 2019 position statement that there is inconclusive evidence whether hormonal contraception may be contributing to changes in sexual desire and sexual dysfunction, it appears that “a minority of women” experience “better or worse sexual functioning” from taking combined oral contraceptives (Both S et al. J Sex Med. 2019 Nov;16[11]:1681-95), suggesting that the majority of women report no significant changes.