Hormonal contraceptives are often associated with the onset of depression. However, how significant is the increased risk of depression due to hormonal contraceptive use?

Can Hormonal Contraceptives cause Depression?
Illustration, A woman gets depression.
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Based on data from 2013-2016, the depression incidence rate in adults over 20 years of age in the United States was 8.1%, in which the female population was more susceptible to depression, with a risk almost twice as high as that of men.

On the other hand, some data showed that girls' depression prevalence at prepubertal age was almost the same for boys. This is one of the basic hypotheses of the influence of hormones (estrogen and progesterone) on the development of depression.

Anderl et al.'s (2019) research suggest that the use of oral hormonal contraceptives during adolescence will increase the risk of depression throughout life compared to those who never use it. However, other scientific evidence produces data that varies, ranging from increased risk, no effect, or decreased risk.


The Link Between Estrogen and Depression

Ovarian hormones play a role in modulating emotional perception, mood regulation, stress response, and cognitive. Periods of low estrogen (naturally occurring during the premenstrual and later stages of perimenopause) are thought to increase depression susceptibility due to withdrawal from modulation of emotional processing and mood regulation.

Estradiol modulates the serotoninergic and cholinergic systems that intersect with the dorsal regulatory system's function. Until now, serotonin and norepinephrine dysregulation is believed to cause depression symptoms. Estradiol increases central norepinephrine levels.

In animal trials that were performed ovariectomy, there was a decrease in estradiol. Furthermore, when more estradiol was added to them,  there was an increase in serotonin receptors in the dorsal raphe nucleus, anterior frontal, and cingulate regions.


The Link Between Progesterone and Depression

Steroid hormone levels are known to affect the digestive system. During the follicular period, high estrogen levels increase peristalsis, and high progesterone levels during the luteal period are associated with constipation. Apart from that, progesterone also affects the composition of bacteria in the digestive and reproductive systems. Progesterone therapy in experimental animals was found to increase Lactobacillus spp. This bacterium is considered an antidepressant effect because it can increase brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus.

Decreased progesterone levels are also associated with: reduced Lactobacillus spp., Increased inflammatory response, and downregulation of BDNF expression, which may increase the risk of depression.



Relationship between Hormonal Contraception and Depression

Some hormonal contraceptives have the effect of lowering estrogen levels by suppressing the hypothalamic-pituitary-ovarian axis. Changes in estrogen levels are thought to trigger depressive episodes in women who have risk factors. Women with major depressive disorder were found to have lower estradiol levels compared to the control group.

Progesterone's addition to combined oral contraceptives has been reported to increase the side effects of mood disorders in those who have previously experienced deterioration in mood and emotional changes due to contraception. The mechanism that is thought to cause progesterone metabolites to the γ-aminobutyric acid A receptor complex plays a role in the major inhibitory system in the human central nervous system.


How significant is the increased risk of depression due to the use of hormonal contraceptives

A national prospective cohort study was undertaken to follow more than 1 million women over 14 years, ranging in age from 15-34 years at study entry and using hormonal contraception. The results of this study indicated that users of combined oral contraceptives had an increased risk of first-time use of antidepressants by 1.2 when compared to people who did not use hormonal contraceptives. 

The following increases the risk of using antidepressants in women using hormonal contraceptives:
  • progestins have an increased risk of 1.3 times
  • the transdermal patch (norelgestromin) increased risk by 2 times
  • implants increased risk 2.1 times
  • levonorgestrel intrauterine system increased risk 1.4 times
  • and medroxyprogesterone acetate depot increased risk 2.7 times.

Meanwhile, when compared to the length of time using hormonal contraceptives with the risk of being diagnosed with depression for the first time, the use of less than 1 month had an increased risk of 1.2 times. Duration of use 1-2 months resulted in an increased risk of 1.3 times; 2-3 months of use increased risk 1.4 times; peaked at 6 months of use with a 1.5-fold increased risk.

After 6 months of use, the risk has decreased, namely 6 months-1 years of 1.2 times; 1-4 years usage by 0.9 times; the use of 4-7 years by 0.8 times; and there is no difference in using 7-10 years.

Another study, a multicentre randomized controlled trial involving 202 healthy women, attempted to compare the mood disorders side effects on the use of combined oral contraceptives containing 1.5 mg estradiol and 2.5 mg nomegestrol acetate with placebo.

This study's results indicate a small significant relation between the use of COCs with the increase of anxiety disorders, irritability, and mood swings in the intermenstrual phase. Related depression, the use of COCs significantly improved depression in the premenstrual phase.

Secondary analysis showed that women with a history of prior hormonal contraceptive-related mood disorders experienced a more significant deterioration in the intermenstrual phase than healthy women. However, this study found that the existing mood deterioration was not clinically significant or relevant.

In addition, the substudy from this clinical trial also found that depression and emotional distress were not associated with hormonal contraceptive use, but rather to baseline anxiety traits and previous history of psychiatric symptoms.



Conclusion
Estrogen and progesterone hormone levels play a role in modulating emotional perception, mood regulation, stress response, and cognitive. On this basis, the use of hormonal contraceptives is thought to be associated with the onset or worsening of depression. The results of a large prospective cohort study in Denmark support this hypothesis. This study found that the use of hormonal contraceptives was significantly associated with an increased risk of taking antidepressants and diagnosing depression at first.

However, a more recent multicentre clinical trial found the opposite result. This clinical trial reports that deterioration of mood associated with hormonal contraceptive use is not clinically significant. The substance reported that the emotional disturbance that appeared was more related to the patient's baseline trait.

Better clinical trials are still needed to determine whether hormonal contraception is indeed associated with clinically significant depression and how the characteristics of women who are more at risk of depression are related to the consumption of hormonal contraceptives. It will be important to educate and monitor the manifestations of depression in patients taking hormonal contraceptives in practice.


References
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