Reliable contraception is a monumental achievement of the last century. Very effective at preventing pregnancy, oral contraceptives, generally referred to as "the Pill," are commonly prescribed to women of reproductive age.
Aside from contraceptive purposes, the Pill can also be used to treat gynecological disorders such as irregular or excessive bleeding, polycystic ovarian syndrome (PCOS), severe menstrual cramping, acne, and endometriosis-associated pain, and their use has been associated with a reduced risk of endometrial cancer.
The Small Print – Side Effects
Since its approval for contraceptive purposes 55 years ago, major changes have been implemented in the composition and dosage of the Pill to reduce side effects without compromising efficacy.[1] Even with these careful stepwise modifications, however, not all of the Pill’s adverse manifestations have been eliminated. Ranging from mild ones such as nausea, weight gain, gastrointestinal disturbances, low libido, and tender breasts, to more severe side effects like high blood pressure, migraines, elevated blood clotting, heart disease, and gallbladder disease, the Pill introduces subtle changes to the equilibrium of one’s body.
For a number of women, these side effects are unbearable. One specific set of symptoms that I would like to discuss today is mood disturbances that may arise as a consequence of being on the Pill. With good reason, one Manhattan psychiatrist, Dr. Kelly Brogan, refers to oral contraceptives as "that naughty little pill," ranking mood and anxiety disorders as some of the most common side effects reported by oral contraceptive users.[2]
Neuroendocrine Functions of Endogenous Estrogen & Progesterone
Hormones enliven us – from conception to birth and beyond, they are the driving force behind every physiological process our bodies experience. Profound changes in hormone levels accompany major transitions in a woman’s lifetime.
Beginning with puberty, estrogen and progesterone levels increase, and become even more elevated during pregnancy with a rapid decline in the postpartum period. During and after perimenopause and menopause, sex hormone levels continue to decrease and remain low. Fluctuations in hormone levels often seem to parallel considerable shifts in mood, rendering some women more vulnerable to developing mood disorders, such as anxiety and depression.
According to the monoamine hypothesis of depression, variations in mood may arise from an imbalance in neurotransmitter levels or alterations in signaling. In reality, depressive symptomatology is unlikely to be restricted to neurotransmitters alone, and probably encompasses many diverse classes of molecules and biological systems, including steroid hormones.[3] Apart from their role in procreation, ovarian hormones elicit important regulatory effects on the central nervous system.
The neuromodulatory role of estrogen and progesterone extends to complex biological processes such as brain development and neuronal plasticity, and plays a critical role in regulating cognition, learning, memory, emotion, mood, and motor control. Modulation of these executive functions occurs either by direct actions of estrogen and progesterone on their receptors,[4] or by interactions with the dominant neurotransmitter systems, such as serotonin, dopamine, GABA and glutamate.[5] Consequently, even subtle shifts in endogenous sex hormones throughout the menstrual cycle can influence variations in mood states.
The Role of Synthetic Hormones on the Central Nervous System
So what happens when a woman takes oral contraceptives? Since the introduction of the Pill five decades ago, the effects of synthetic hormones on emotions, cognition, and memory have remained largely unexplored.
Just recently, the effects the Pill elicits on women’s bodies started to be addressed. For starters, oral contraceptives deplete the body of important vitamins and minerals. B vitamins (necessary cofactors in neurotransmitter production) and the essential trace elements selenium, magnesium, phosphorus and zinc can plummet with continuous use of the Pill, meanwhile cadmium, calcium, iron (can induce oxidative stress), and copper levels (low zinc and high copper may lead to a multitude of ailments, including fatigue, depression, PMS, insomnia, headaches, hypertension, and many others) can increase dramatically.[2][6]
Additionally, synthetic hormones in the Pill centrally disrupt the hypothalamic-pituitary-ovarian axis and locally inhibit ovarian production of estrogen, progesterone,[7] and testosterone.[8] The Pill also decreases hypothalamic-pituitary-adrenal axis activity and the response of the adrenal hormone cortisol.[9] Other recently emerging studies report that oral contraceptives induce significant structural and functional transformations in the brain. Women on the Pill present with considerable increases in the volume of gray matter in cortical regions[10] and in cerebral white matter,[11] areas of the brain responsible for processing emotions.
Effects on Mood & Behavior
So how do structural changes translate to functional presentation, i.e., changes in mood and behavior? Women using oral contraceptives may exhibit personality changes such as altered emotional memory,[12] recognition of anger, and risky decision making compared to naturally-cycling controls.[13] The precise mechanism of how synthetic hormones modify brain structure and function are not known and will require extensive research in the future.
Individual Variations in Vulnerability to Depressive Side Effects
In the meantime, all this still begs the question – why do some women respond well to oral contraceptives in terms of mood symptoms, and others acknowledge that depression is the biggest factor in their decision to discontinue the Pill? Who are the women that are more vulnerable to the pharmacological burden of oral contraceptives?
The answer may be complex and multifaceted, not well understood, and partially yet undiscovered. For starters, it appears that women with a predisposition to psychiatric disorders (personal or family history) for whom exacerbation of mood pathology coincides with hormonal fluctuations (pregnancy, postpartum, or starting the Pill at a young age) may be more susceptible to developing adverse psychiatric symptoms when on the Pill.[2] And the other answer (one of many more) is genetics.
A recent study published in Neuroscience explored the role of the mineralocorticoid receptor (MR) in processing of emotional information in Pill users and non-users.[13] Oral contraceptives suppress cortisol secretion by modifying cortisol feedback to the brain, which is mediated by the mineralocorticoid receptor (MR). MRs are located in brain areas crucial for processing stressful information (cortex, amygdala, and hippocampus) and serve as important targets when studying reactions to psychological stress, such as emotional expression, vigilance, selective attention, and emotional memory. MRs can be expressed as haplotypes 1, 2, or 3. The authors report that oral contraceptive use is associated with a depressogenic side effect presentation. However, those users of the Pill who expressed MR haplotype 2 were protected against the negative effects of synthetic hormones on memory and perception. This study offers a glimpse into identifying one key piece of the intricate puzzle that encompasses mood disorders and explain why some but not all women experience mood swings when using the Pill.
Oral contraceptives are not a one-size-fits-all kind of an entity. There are many different combinations of synthetic estrogens and progestins that comprise the Pill. Figuring out which kind might be right for your patient might take time, keeping in mind that it is possible that some patients may not be able to tolerate oral contraceptives at all.
Learn about Neurotransmitter Testing
References
[1] Dhont,M. (2010) History of oral contraception. Eur. J. Contracept. Reprod. Health Care 15 Suppl 2, S12-S18
[2] Kelly Brogan,M. (2016) A Mind of Your Own, HarperCollins Publishers
[3] Hindmarch,I. (2002) Beyond the monoamine hypothesis: mechanisms, molecules and methods. Eur. Psychiatry 17 Suppl 3, 294-299
[4] Engler-Chiurazzi,E.B. et al. (2016) Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog. Neurobiol.
[5] Barth,C. et al. (2015) Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Front Neurosci. 9, 37
[6] Pamela Wartian Smith (2008) What You Must Know About Vitamins, Minerals, Herbs & More. Choosing The Nutrients That Are Right For You., Square One Publishers
[7] De,B.T. et al. (2013) Regional gray matter volume differences and sex-hormone correlations as a function of menstrual cycle phase and hormonal contraceptives use. Brain Res. 1530, 22-31
[8] Zimmerman,Y. et al. (2014) The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis. Hum. Reprod. Update. 20, 76-105
[9] Nielsen,S.E. et al. (2013) Hormonal contraception use alters stress responses and emotional memory. Biol. Psychol. 92, 257-266
[10] Pletzer,B. et al. (2010) Menstrual cycle and hormonal contraceptive use modulate human brain structure. Brain Res. 1348, 55-62
[11] De,B.T. et al. (2013) Does the use of hormonal contraceptives cause microstructural changes in cerebral white matter? Preliminary results of a DTI and tractography study. Eur. Radiol. 23, 57-64
[12] Nielsen,S.E. et al. (2011) Hormonal contraception usage is associated with altered memory for an emotional story. Neurobiol. Learn. Mem. 96, 378-384
[13] Hamstra,D.A. et al. (2015) Mineralocorticoid receptor haplotype, oral contraceptives and emotional information processing. Neuroscience 286, 412-422
