The Pill and Potential Link to Mood Concerns

Many women take the contraceptive pill, and not just for contraception, so are you potentially damaging your health?


I am always interested in the potential that synthetic hormones have for impacting on women’s health.

So in order to bring a new perspective, I am happy to reproduce this article with permission from Doctors Data by Ruth Hobson, ND.

This is more technical than our usual articles, as it is aimed at medical professionals, but I think there is much value for the lay reader and I hope you also find it helpful.

The background

Oral contraceptives (OCPs) have become a ubiquitous part of the modern healthcare system with an estimated 151 million women utilizing them worldwide in 2019. While these medications are listed as essential, recent exploration of potential mood-altering side effects has demonstrated there may be more than ovulation suppression going on.

It is well known that estrogen and progesterone can influence the brain as well as mood regulation. In addition to their role as sex steroids, these hormones are also known as neurosteroids with receptors located throughout the brain, particularly in areas of emotional and cognitive processing. OCPs come in a variety of combinations of strengths as well as estrogens and progestogens.

It should be noted that OCPs do not contain progesterone. Instead, OCPs contain a combination of an estrogen and progestin or even a progestin only.

Progestins and mood

Because progestins have a somewhat similar structure to progesterone, they can bind to progesterone receptors resulting in ovulation suppression.

Progestins are an effective contraceptive tool, but the question remains, “Could progestins be to blame for some of the negative mood concerns demonstrated with OCPs?”

The enzyme monoamine oxidase (MAO) is involved in the breakdown of serotonin, dopamine, norepinephrine, and epinephrine. Studies have demonstrated that progestins, more than progesterone, increase MAO activity leading to a surge in the degradation of serotonin and the catecholamines, and is possibly why some women report mood altering effects with OCP usage.

While the research is mixed in this area, reports of low dose progestin-only pill use in teens has been shown to increase the use of antidepressants when compared with other nonuser teens. A randomized controlled trial was conducted by Zethraeus et al to determine if there was a causal relationship between the use of OCP treatment on general well-being and depressed mood in healthy women.

While there was a statistically significantly difference in reported wellbeing, depressive symptoms were not determined to be statistically significant. Although researchers have not discovered the causality of depression and OCPs, continued research in this area should be considered when prescribing them.

Hormones and stress-related disorders

A 2017 study has taken the research from examining sex hormones directly and expanded it to the HPA axis. Understanding that some link must exist between OCPs and stress-related disorders like depression, Hertel et al hypothesized that OCPs might deregulate the HPA axis by increasing circulating cortisol levels.

By examining genes related to glucocorticoid upregulation, researchers were able to determine cortisol upregulation can occur as well as an upregulation of proteins associated with psychiatric disease.

Additionally, researchers examined hippocampal volume using MRI of OCP users and non-users and found significantly smaller hippocampal volumes in the OCP group compared with non-users. Because smaller hippocampal volumes have been discovered in those with chronic stress, Hertel may have discovered another piece of the puzzle when it comes to the mood and quality of life concerns seen in some women taking OCPs.

Although this data did not demonstrate specific causality, continued research in this area may provide a better understanding of the full physiologic effects of OCPs.

Based on this research, consider HPA axis screening in combination with a comprehensive examination of neurotransmitters for your patients on OCPs. Results may indicate the need for further testing of MAO activity. Because dysregulation of both neurotransmitters and the HPA axis can present with similar and overlapping symptoms, pinpointing specific imbalances may help guide your treatment and support your patients on OCPs.

Note: Providers often ask about the utility of testing sex hormones in women on OCPs. Because ovulation is suppressed with OCP use, results usually reflect low to low range estradiol and progesterone levels, as synthetic progestins are not measured by laboratory test systems. Many providers choose to test in order to show patients how OCPs manipulate hormones and how low levels correspond with symptoms, which can inform future treatment.


1. United Nations, Department of Economic and Social Affairs, Population Division (2019). Contraceptive Use by Method 2019: Data Booklet (ST/ESA/SER.A/435)

2. Toffoletto S, Lanzenberger R, Gingnell M, Sundström-Poromaa I, Comasco E. Emotional and cognitive functional imaging of estrogen and progesterone effects in the female human brain: a systematic review. Psychoneuroendocrinology. 2014;50:28-52.

3. Klaiber EL, Broverman DM, VogelW, Peterson LG, Snyder MB. Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women. Psychoneuroendocrinology. 1996;21(7):575-592.

4. Wiréhn AB, Foldemo A, Josefsson A, Lindberg M. Use of hormonal contraceptives in relation to antidepressant therapy: a nationwide population-based study. Eur J Contracept Reprod Health Care. 2010;15(1):41-47.

5. Hertel, J., Koing, J., Homuth, G. et al. Evidence for Stress-like Alterations in the HPA-Axis in Women Taking Oral Contraceptives. Sci Rep 7, 14111 (2017). https://