This study found that depression was disproportionately associated with adverse event reports of levonorgestrel, etonogestrel, medroxyprogesterone, and desogestrel. This study found that depression was disproportionately associated with adverse event reports of levonorgestrel, etonogestrel, medroxyprogesterone, and desogestrel. Levonorgestrel and medroxyprogesterone showed positive signals in PRR, ROR, IC025 and EBGM05, suggesting a strong correlation between these drugs and depression. ROR and PRR of etonogestrel showed positive signals, while IC025 and EBGM05 showed negative signals, suggesting a slight correlation between etonogestrel and depression. Desogestrel due to the small sample size. The PRR, ROR, IC025 and EBGM05 of hydroxyprogesterone, progesterone and megestrol were all negative. However, there are few records of hydroxyprogesterone, progesterone and megestrol in the FAERS database. Therefore, it is not possible to determine the association between these drugs and depression through the available data.
A study of French women showed that 38.8% of women using levonorgestrel-releasing intrauterine device (LNG-IUD) experienced symptoms of depression over a two-year period after LNG-IUD-related adverse reactions were brought to the attention of the French media[17]. A retrospective review of levonorgestrel related adverse events recorded in the FAERS database between 2004 and 2015 suggests that there may be a risk of postpartum depression associated with the use of progestogen or LNG-IUD[18]. A study of the clinical efficacy of an LNG-IUD found that of 678 women who used an LNG-IUD, 13 developed depression over a 5-year period[19]. A survey of LNG-IUD users also showed an association between levonorgestrel and depression, with more than 17,000 users taking part in the survey, 36% of whom experienced depression while using LNG-IUD. Although the results of this questionnaire are not sufficient to prove a correlation between levonorgestrel and depression, the incidence of depression in people using LNG-IUD is as high as 36%, which still requires sufficient attention. Another partially randomized trial of 1,600 LNG-IUD users showed that 5.4% of users developed depression or depressive mood[20]. In addition, several reports suggest that depression or mood swings are one of the important reasons leading to the discontinuation of LNG-IUD[21–25].
However, there are some studies that do not support a correlation between levonorgestrel and depression. One report with a sample size of 350 women showed no significant difference in depression scores among women using LNG-IUD compared to women with copper-containing iuds[26]. Another study of 120 premenopausal women using LNG-IUD showed no significant difference in depression scores compared to baseline[27]. Our results showed that out of more than 436,000 records of levonorgestrel adverse events in the FAERS database, 4,517 were recorded for depression. ROR,PRR,BCPNN, and MGPS all showed positive signals between levonorgestrel and depression, suggesting that there is a significant correlation between Levonorgestrel and depression. Although the current research on the correlation between levonorgestrel and depression is still controversial, our study of a large number of adverse reactions recorded in the FAERS database showed a strong pharmacovigilance signal between levonorgestrel and depression, so we believe that the occurrence of depression during the use of levonorgestrel should be paid attention.
Medroxyprogesterone is a progestogen drug that is administered by injection and oral. The Current research on the association between medroxyprogesterone and depression is a topic of controversy. A cohort study of medroxyprogesterone assigned a CESD score to 80 women using medroxyprogesterone, with a CESD score over 16 indicating depression. The results of the study showed that women using medroxyprogesterone had a CESD score of 15.6, which did not meet the diagnostic criteria for depression, but medroxyprogesterone still increased the risk of depression[28]. A randomized controlled study of women using medroxyprogesterone using the Edinburgh Postnatal Depression Scale (EPDS) and BDI score showed a poor EPDS score after 1 month of medroxyprogesterone use and a poor BDI score after 3 months of medroxyprogesterone use, and these results showed an increased risk of depression with short-term medroxyprogesterone use[29]. These findings are consistent with our study. However, some studies have shown that medroxyprogesterone may reduce the risk of depression. A study of perimenopausal and postmenopausal women showed that short-term use of medroxyprogesterone did not increase the risk of depression[30]. However, it is important to note that our study showed a strong pharmacovigilance signal between levonorgestrel and depression, but no positive signal between levonorgestrel and major depression. Medroxyprogesterone has positive signals with both depression and major depression. In addition, the results of age-stratified analysis indicate that medroxyprogesterone exhibits a positive signal in individuals under the age of 18. Therefore, clinicians should pay attention to the occurrence of depressive symptoms when using medroxyprogesterone. More importantly, although none of the seven progestogen, including levonorgestrel and medroxyprogesterone, showed a negative pharmacovigilance signal for suicide and self-harm, medroxyprogesterone showed a positive pharmacovigilance signal for suicidal thoughts. At the same time, of the 436,000 adverse events recorded for levonorgestrel, there were 18 successful suicides, but of the 48,000 adverse events recorded for medroxyprogesterone, there were 5 successful suicides. Although our results did not find a positive pharmacovigilance signal between progestogen and suicide completion, but medroxyprogesterone has shown a positive pharmacovigilance signal in suicidal thoughts, so clinical use of medroxyprogesterone should be vigilant against possible suicidal behavior. In the FAERS database, 85.4% of patients used levonorgestrel as an IUD, while patients used medroxyprogesterone as an injection. Compared with Iuds, injection has a greater effect on the central nervous system. Therefore, we speculate that the reason for the higher risk of depression caused by medroxyprogesterone may be related to the mode of administration.
Although depression mechanism of action by which progestogen causes depression has not been fully elucidated. A previous study has shown that LNG-IUD users have significantly increased responsiveness to psychosocial stress, which is closely related to the absorption of levonorgestrel released by LNG-IUD into the blood. Levonorgestrel entering the blood circulation can affect the hypothalamic/pituitary axis, which can adversely affect mood[31]. A basic study in rats has shown that 17α-hydroxyprogesterone caproate inserted into progesterone receptors in the medial prefrontal cortex during development in rats caused damage to the medial prefrontal cortex serotonergic nerve, thereby affecting 5-HT nerve-mediated behavior[32]. Since the decline of 5-HT function is considered to be one of the important mechanisms of depression, this report suggests that progesterone may have a certain correlation with the occurrence of depression.
Admittedly, there are some limitations to our study. First of all, the FAERS database is a spontaneous reporting system for adverse reactions, and some reporters may lack information when filling in the information related to adverse reactions, which will lead to the loss of some valid data. Second, only information about adverse reactions was recorded in the FAERS database, and information about drug users who did not experience adverse reactions was not included, so our study could not calculate the exact incidence of adverse reactions. Many confounding factors prevented us from further studying the correlation between adverse reactions and clinical features. Third, since progestogen is used in combination with other drugs in some cases, but our study did not consider accompanying drugs, the next step will be to study drug interaction. Although our study has some limitations, but the FAERS database recorded 6,550 adverse events related to progesterone induced depression, so our study can provide important reference information for the practical application of progestogen in clinical practice.