Pharmacovigilance study of the association between progestogen and depression based on the FDA Adverse Event Reporting System (FAERS)

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Progestogenare widely used in the treatment of contraception, endometriosis, threatened abortion and other diseases. However, the correlation between progestogenand depression is not clear. Therefore, this study used the FDA Adverse Event Reporting System (FAERS) database to assess the relationship between progestogenand depression. Methods: In this study, all data from the first quarter of 2004 to the secondquarter of 2024were extracted and imported into SAS9.4 software for data cleaning and analysis. Report Odds ratio (ROR), Proportional Report ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and Multi-item Gamma Poisson Contraction-machine (MGPS) were used for Bayesian analysis and disproportionation analysis. Results: Levonorgestrel, medroxyprogesterone, etonogestrel and desogestrel showed positive signs of depression, and medroxyprogesterone also showed positive signs of major depression. Although none of the progestogenshowed a positive sign for suicide and self-harm, medroxyprogesterone showed a positive sign for suicidal thoughts. Conclusion: Analysis of data from FAERS database showed that levonorgestrel, medroxyprogesterone, etonogestrel, desogestrel were correlated with depression. These findings provide real-world evidence of the potential risk of progestogen-related depression. Biological sciences/Drug discovery/Drug safety Health sciences/Health care/Therapeutics Depression Progestogen Pharmacovigilance Adverse event reporting system Epidemiology Figures Figure 1 1. Introduction Depression is one of the highest incidence of mental illness, previous studies have shown that the incidence of depression in women is more than twice that of men[ 1 ].About 17 percent of women will suffer from depression in their lifetime[ 2 ].The number of women who did not meet the clinical criteria for depression but had depression was higher[ 3 ].Depression and depressed mood have a serious negative impact on women's mental health. Progestogen are the most commonly used contraceptive drugs for women, according to statistics, more than half of women in reproductive age in the United States choose to use progestogen for contraception[ 4 ].In addition to the use of contraception, in the treatment of functional uterine bleeding, dysmenorrhea, endometriosis, threatened abortion and other obstetrical and gynecological diseases, progestogen have also been widely used[ 5 – 7 ].When used as contraception, progestogen drugs can not only produce satisfactory contraceptive effects, but also bring some health benefits for women of reproductive age, but it also comes with some risks[ 8 ].Common adverse effects of progestogen include fluid retention, weight gain or loss, and acne[ 9 , 10 ].In addition to these common adverse effects, progestogen may have emotional effects on women, including depression and anxiety[ 11 ].Epidemiological studies show that women are twice as likely to suffer from depression as men[ 12 ], the link between progestogen and depression has attracted much attention. Although a number of clinical investigations have explored the relationship between progestogen drugs and depression, different studies have reached inconsistent conclusions. Progestogen drugs is often used as a contraceptive measure for postpartum women[ 13 ].At the same time, postpartum women are at high risk for depression[ 14 ], and these factors make the correlation between progesterone and depression difficult to determine. The FDA adverse events reporting system (FARES) is a database that collects information on self-reported adverse events (AEs). The collection of self-reported adverse drug reaction records from 2004 to the present is an important data source for post-marketing adverse drug reaction signal mining research[ 15 , 16 ].Therefore, this study will conduct a retrospective pharmacovigilance study on depression caused by progestogen commonly used in a large number of people through FARES database, excavate potential pharmacovigilance signals, evaluate their safety, and provide references for clinical rational drug use. 2. Methods 2.1.Data source Data came from the FAERS database. The FAERS database has been releasing data packets on a quarterly basis since the first quarter of 2004. All the ASCII data packets of 82 quarters from the first quarter of 2004 to the second quarter of 2024 were downloaded and imported them into SAS9.4 software for data cleaning and analysis. 2.2.Target drug population screening Each patient has a unique "Primary Suspect Drug (PS)" in the database. When determining the target drug use population, only the drug that the patient first suspects is considered. If the drug suspected by the patient is the target drug of the study in the background database of the analysis, the target drug population is included, and other patients are included in the other drug population. The drug name and active ingredient (PROD_AI) in FAERS database were standardized by WHO DRUG dictionary, and the standardized names were used to screen target drugs. 2.3.Data processing Select the PRIMARYID, CASEID, and FDA_DT fields in the DEMO table and sort them by CASEID, FDA_DT, and PRIMARYID. For reports with the same CASEID, retain the largest FDA_DT value. If CASEID and FDA_DT are the same, reserve the largest PRIMARYID value. Since the names of adverse events recorded in the FAERS database use preferred terms (PT) from the medical dictionary for regulatory activities (MedDRA), which is updated annually in March and September, Each update involves PT level adjustments and system organ class (SOC) changes, so PT names in the FAERS database are corrected using the latest version of the MedDRA dictionary.Depression cases were obtained by searching using MedDRA 28.0, and the PT include depression, depression suicidal, major depression, menopausal depression, persistent depressive disorder, perinatal depression, mixed anxiety and depressive disorder.Pharmacovigilance signals were calculated after the combination of PT. Study drugs were progestogen (levonorgestrel, etonogestrel, medroxyprogesterone, hydroxyprogesterone, progesterone, desogestrel, megestrol) on the market. After processing the raw data, we got 6,550 reports. The specific process is shown in Figure 1. 2.4. Statistical Analysis Construct a two-by-two contingency table for signal detection of adverse events. The composition of the two-by-twol table is shown in Table 1. Reporting Odds Ratio (ROR), Proportional Reporting Ratio, (PRR), Bayesian confidence propagation neural network (BCPNN), and Muti-item Gamma Poisson Shrinker (MGPS) detect signals of adverse drug events. If ROR a≥3 and 95% CI(lower limit) > 1 prompts one signal to be generated, PRR a≥3 and 95% CI(lower limit) > 1 prompts one signal to be generated, and BCPNN lower limit of confidence interval (IC-2SD) > 0 prompts one signal to be generated. If MGPS EBGM05 > 2, a signal is generated. 3. Results 3.1. Descriptive Analysis The FAERS database included 6,550 cases of progestogen-related depression from the first quarter of 2004 through the second quarter of 2024. The demographic characteristics of patients with progestogen-related depression are shown in Table 2. Patients aged 18-45 years were the main reporting group. Reported cases showed an upward trend before 2017, reaching a peak in 2017, and the number of reported cases gradually decreased after 2017. Cases have been reported mainly in North America and Europe, with consumers being the main reporters of progestogen-related depression. Levonorgestrel had the largest number of cases, followed by etonogestrel and medroxyprogesterone. 3.2. Disproportionality Analysis and Bayesian Analysis Analysis result showed that only a subset of progestogen showed an association with depression. Levonorgestrel, medroxyprogesterone and desogestrel show positive signals in all the four algorithms. Hydroxyprogesterone, progesterone and megestrol did not show positive signals. ROR, PRR and IC of etonogestrel showed positive signals, while EBGM showed negative signals. The correlation between different progestogen and depression was ranked as follows: levonorgestrel (ROR=2.72, 95%CI: 2.64-2.80) > medroxyprogesterone (ROR=2.37, 95%CI: 2.16-2.59) > desogestrel (ROR=2.08, 95%CI: 1.18-3.67) > etonogestrel (ROR=1.72, 95%CI: 1.63-1.83) > progesterone (ROR=0.88, 95%CI: 0.60-1.27) > hydroxyprogesterone (ROR=0.80, 95%CI: 0.68-0.943) > megestrol (ROR=0.54, 95%CI: 0.24-1.21) (table 3). The relationship between progestogen and major depression was analyzed. The results showed that only medroxyprogesterone showed positive signals in four algorithms, and the other progestogen did not show positive signals(table 4).Analysis of suicide and self-harm showed no positive signal for any of the progestogen(table 5).However, the analysis results of medroxyprogesterone in suicidal thoughts showed that ROR (ROR=1.65, 95%CI: 1.38-1.98), PRR (PRR=1.65, 95%CI: 1.38-1.97) and IC (IC=0.72, IC025=0.45) showed positive signals (table 6). 3.3. Outcomes due to Depression These outcomes encompass life threatening, hospitalization, disability, death, congenital anomaly, required intervention to prevent permanent impairment damage and other adverse events. Among them, the number of adverse reactions associated with progesterone, desogestrel and megestrol was below 30 cases; thus the reference value is significantly limited. Among drugs with over 100 reported adverse reactions, hydroxyprogesterone exhibited the lowest incidence of life threatening (0.7%), while the remaining three progestogens showed minimal variation. Levonorgestrel demonstrated the highest hospitalization rate (32.1%), whereas etonogestrel had the lowest hospitalization rate (9.5%). Although most progestogens have a low mortality rate attributed to depression, medroxyprogesterone displayed a mortality rate of 1.4%, surpassing that of other medications. (table 7). 3.4. Hierarchical analysis based on age subgroups Levonorgestrel-related depression showed a positive signal in individuals aged 18-44 and 45-64 across all four algorithms. Etonogestrel-related depression exhibited positive signals in individuals under 18 years old and those aged 18-44, as indicated by ROR, PRR, and IC algorithms; however, EBGM algorithm did not detect any positive signals. Medroxyprogesterone-related depression demonstrated a positive signal in individuals under 18 years old and those aged 18-44 according to all four algorithms. In the age group of 45-64, only the PRR algorithm detected a positive signal while the remaining three algorithms did not show any. Individuals older than 65 years displayed positive signals for hydroxyprogesterone, progesterone, desogestrel, and megestrol based on ROR, PRR, and IC algorithms; however, EBGM algorithm did not indicate any positive signals. (Table 8). 3.5.Onset times of Depression After the use of progestogen drugs, the time of onset of depression is within 180 days. A lower proportion of depression occurred after 180 days of progestogen use. This suggests that when progestogen drugs are used, the time of onset of depression is mainly within 180 days of medication. However, it is worth noting that a small number of patients still develop depression after 5 years, with medroxyprogesterone having the highest rate (7.7%) (Table 9). 4. Discussion 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. 5. Conclusions The results of this study showed that levonorgestrel, medroxyprogesterone and etonogestrel showed positive pharmacovigilance signals associated with depression. Medroxyprogesterone also showed a positive pharmacovigilance signal associated with suicidal thoughts.We recommend that clinicians monitor for depression-related symptoms when using the aforementioned progestogen. At the same time, due to the small sample size, more clinical studies are needed to confirm the safety of progesterone, desogestrel and megestrol. Declarations Data availability: All data is publicly available on the FDA website (https:// fis. fda. gov/ exten sions/ FPD- QDE- FAERS/ FPD- QDE- FAERS. html). Author Contributions : Hui Gao was responsible for the design of the research, experimental data analysis, and manuscript preparation.Xiaohan Zhai and Yan Hu were responsible for the interpretation of data. Hang Wu was responsible for designed and directed the research. Funding : Funding for this research came from project ZR2022QC167 supported by Shandong Provincial Natural Science Foundation and project XY20BS11 supported by Heze University doctoral Fundation. 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Supplementary Files rawdata.rar Tables.doc Cite Share Download PDF Status: Published Journal Publication published 08 Jan, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 05 Nov, 2024 Reviews received at journal 06 Oct, 2024 Reviewers agreed at journal 26 Sep, 2024 Reviewers invited by journal 19 Sep, 2024 Editor assigned by journal 18 Sep, 2024 Editor invited by journal 07 Jul, 2024 Submission checks completed at journal 04 Jul, 2024 First submitted to journal 25 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4639254","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":331829621,"identity":"3fdd1879-9042-46b9-9a4f-da8ea4f831be","order_by":0,"name":"Hui Gao","email":"","orcid":"","institution":"Heze Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Gao","suffix":""},{"id":331829623,"identity":"737c7cdf-40df-4928-9642-b640e3a580df","order_by":1,"name":"Xiaohan Zhai","email":"","orcid":"","institution":"The First Affiliated Hospital of Dalian Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaohan","middleName":"","lastName":"Zhai","suffix":""},{"id":331829624,"identity":"3a49cc84-d566-4add-a66a-df374b45a1b0","order_by":2,"name":"Yan Hu","email":"","orcid":"","institution":"The Second Affiliated Hospital of Dalian Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Hu","suffix":""},{"id":331829628,"identity":"78172cae-44c6-4744-9015-bec250a5471c","order_by":3,"name":"Hang Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYFACHhAhIccv/7D9Q+IfGx5+/gaitFgYSzYkH2P42JAmIznjAFFaKhI3HEhLY5zZcNjGoCEBvwaDG7kHPxf8kkic2XDG7DHvjvM8BgwHGD98zMGnJS9ZemafhHE/Y4+5Me+Z2zzmzA3MkjO34dZidiPHQJq3R0J2ZjOPgTQP220ey4YDbMy8+LUY/wZqYdxwDKzlHI/BgQSCWsykeX5IKG44w5YmObPtAGEt9mfemFnzNkgYS85gPmzw4Uwyj+SMg814/SLZnmN8m+dPnRy/BGPjg4QKO3t+/uaDHz7i0QIGjG2o3AYC6kHgDxFqRsEoGAWjYOQCAAO5VjcOaqCIAAAAAElFTkSuQmCC","orcid":"","institution":"Heze University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hang","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2024-06-26 02:03:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4639254/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4639254/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-85826-1","type":"published","date":"2025-01-08T15:58:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":61301781,"identity":"9ec48586-b691-433a-8e8e-485f767e18e9","added_by":"auto","created_at":"2024-07-29 09:06:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65638,"visible":true,"origin":"","legend":"\u003cp\u003eThe process of selecting cases of pregnancy-related depression from the FAERS database. DEMO, demographic information; DRUG, drug information; REAC, adverse event.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4639254/v1/b10119e6f8e4037851eb902f.png"},{"id":73694408,"identity":"1ba41bc7-ce7c-4eb5-9698-fe7ddde66027","added_by":"auto","created_at":"2025-01-13 16:13:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":418303,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4639254/v1/fadf8375-97be-4a24-85ad-59040a51aaae.pdf"},{"id":61301783,"identity":"e55bb794-3d83-4b92-ad60-4a562d30da39","added_by":"auto","created_at":"2024-07-29 09:06:49","extension":"rar","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2208210,"visible":true,"origin":"","legend":"","description":"","filename":"rawdata.rar","url":"https://assets-eu.researchsquare.com/files/rs-4639254/v1/c64d293ecf43cdf0e219c177.rar"},{"id":61301782,"identity":"743b4f73-8c0f-4131-957e-33c5617d42e6","added_by":"auto","created_at":"2024-07-29 09:06:49","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":199168,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.doc","url":"https://assets-eu.researchsquare.com/files/rs-4639254/v1/28a9350ffea64fad20ae9b97.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pharmacovigilance study of the association between progestogen and depression based on the FDA Adverse Event Reporting System (FAERS)","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eDepression is one of the highest incidence of mental illness, previous studies have shown that the incidence of depression in women is more than twice that of men[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].About 17 percent of women will suffer from depression in their lifetime[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].The number of women who did not meet the clinical criteria for depression but had depression was higher[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].Depression and depressed mood have a serious negative impact on women's mental health.\u003c/p\u003e \u003cp\u003eProgestogen are the most commonly used contraceptive drugs for women, according to statistics, more than half of women in reproductive age in the United States choose to use progestogen for contraception[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].In addition to the use of contraception, in the treatment of functional uterine bleeding, dysmenorrhea, endometriosis, threatened abortion and other obstetrical and gynecological diseases, progestogen have also been widely used[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].When used as contraception, progestogen drugs can not only produce satisfactory contraceptive effects, but also bring some health benefits for women of reproductive age, but it also comes with some risks[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].Common adverse effects of progestogen include fluid retention, weight gain or loss, and acne[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].In addition to these common adverse effects, progestogen may have emotional effects on women, including depression and anxiety[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].Epidemiological studies show that women are twice as likely to suffer from depression as men[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], the link between progestogen and depression has attracted much attention.\u003c/p\u003e \u003cp\u003eAlthough a number of clinical investigations have explored the relationship between progestogen drugs and depression, different studies have reached inconsistent conclusions. Progestogen drugs is often used as a contraceptive measure for postpartum women[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].At the same time, postpartum women are at high risk for depression[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and these factors make the correlation between progesterone and depression difficult to determine.\u003c/p\u003e \u003cp\u003eThe FDA adverse events reporting system (FARES) is a database that collects information on self-reported adverse events (AEs). The collection of self-reported adverse drug reaction records from 2004 to the present is an important data source for post-marketing adverse drug reaction signal mining research[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].Therefore, this study will conduct a retrospective pharmacovigilance study on depression caused by progestogen commonly used in a large number of people through FARES database, excavate potential pharmacovigilance signals, evaluate their safety, and provide references for clinical rational drug use.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003e2.1.Data source\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData came from the FAERS database. The FAERS database has been releasing data packets on a quarterly basis since the first quarter of 2004. All the ASCII data packets of 82 quarters from the first quarter of 2004 to the second quarter of 2024 were downloaded and imported them into SAS9.4 software for data cleaning and analysis.\u003c/p\u003e\n\u003cp\u003e2.2.Target drug population screening\u003c/p\u003e\n\u003cp\u003eEach patient has a unique \u0026quot;Primary Suspect Drug (PS)\u0026quot; in the database. When determining the target drug use population, only the drug that the patient first suspects is considered. If the drug suspected by the patient is the target drug of the study in the background database of the analysis, the target drug population is included, and other patients are included in the other drug population. The drug name and active ingredient (PROD_AI) in FAERS database were standardized by WHO DRUG dictionary, and the standardized names were used to screen target drugs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.3.Data processing\u003c/p\u003e\n\u003cp\u003eSelect the PRIMARYID, CASEID, and FDA_DT fields in the DEMO table and sort them by CASEID, FDA_DT, and PRIMARYID. For reports with the same CASEID, retain the largest FDA_DT value. If CASEID and FDA_DT are the same, reserve the largest PRIMARYID value. Since the names of adverse events recorded in the FAERS database use preferred terms (PT) from the medical dictionary for regulatory activities (MedDRA), which is updated annually in March and September, Each update involves PT level adjustments and system organ class (SOC) changes, so PT names in the FAERS database are corrected using the latest version of the MedDRA dictionary.Depression cases were obtained by searching using MedDRA 28.0, and the PT include depression, depression suicidal, major depression, menopausal depression, persistent depressive disorder, perinatal depression, mixed anxiety and depressive disorder.Pharmacovigilance signals were calculated after the combination of PT. Study drugs were progestogen (levonorgestrel, etonogestrel, medroxyprogesterone, hydroxyprogesterone, progesterone, desogestrel, megestrol) on the market. After processing the raw data, we got 6,550 reports. The specific process is shown in Figure 1.\u003c/p\u003e\n\u003cp\u003e2.4. Statistical Analysis\u003c/p\u003e\n\u003cp\u003eConstruct a two-by-two contingency table for signal detection of adverse events. The composition of the two-by-twol table is shown in Table 1. Reporting Odds Ratio (ROR), Proportional Reporting Ratio, (PRR), Bayesian confidence propagation neural network (BCPNN), and Muti-item Gamma Poisson Shrinker (MGPS) detect signals of adverse drug events. If ROR a\u0026ge;3 and 95% CI(lower limit) \u0026gt; 1 prompts one signal to be generated, PRR a\u0026ge;3 and 95% CI(lower limit) \u0026gt; 1 prompts one signal to be generated, and BCPNN lower limit of confidence interval (IC-2SD) \u0026gt; 0 prompts one signal to be generated. If MGPS EBGM05 \u0026gt; 2, a signal is generated.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e3.1. Descriptive Analysis\u003c/p\u003e\n\u003cp\u003eThe FAERS database included 6,550 cases of progestogen-related depression from the first quarter of 2004 through the second quarter of 2024. The demographic characteristics of patients with progestogen-related depression are shown in Table 2. Patients aged 18-45 years were the main reporting group. Reported cases showed an upward trend before 2017, reaching a peak in 2017, and the number of reported cases gradually decreased after 2017. Cases have been reported mainly in North America and Europe, with consumers being the main reporters of progestogen-related depression. Levonorgestrel had the largest number of cases, followed by etonogestrel and medroxyprogesterone.\u003c/p\u003e\n\u003cp\u003e3.2. Disproportionality Analysis and Bayesian Analysis\u003c/p\u003e\n\u003cp\u003eAnalysis result showed that only a subset of progestogen showed an association with depression. Levonorgestrel, medroxyprogesterone and desogestrel show positive signals in all the four algorithms. Hydroxyprogesterone, progesterone and megestrol did not show positive signals. ROR, PRR and IC of etonogestrel showed positive signals, while EBGM showed negative signals. The correlation between different progestogen and depression was ranked as follows: levonorgestrel (ROR=2.72, 95%CI: 2.64-2.80) \u0026gt; medroxyprogesterone (ROR=2.37, 95%CI: 2.16-2.59) \u0026gt; desogestrel (ROR=2.08, 95%CI: 1.18-3.67) \u0026gt; etonogestrel (ROR=1.72, 95%CI: 1.63-1.83) \u0026gt; progesterone (ROR=0.88, 95%CI: 0.60-1.27) \u0026gt; hydroxyprogesterone (ROR=0.80, 95%CI: 0.68-0.943) \u0026gt; megestrol (ROR=0.54, 95%CI: 0.24-1.21) (table 3). The relationship between progestogen and major depression was analyzed. The results showed that only medroxyprogesterone showed positive signals in four algorithms, and the other progestogen did not show positive signals(table 4).Analysis of suicide and self-harm showed no positive signal for any of the progestogen(table 5).However, the analysis results of medroxyprogesterone in suicidal thoughts showed that ROR (ROR=1.65, 95%CI: 1.38-1.98), PRR (PRR=1.65, 95%CI: 1.38-1.97) and IC (IC=0.72, IC025=0.45) showed positive signals (table 6).\u003c/p\u003e\n\u003cp\u003e3.3. Outcomes due to Depression\u003c/p\u003e\n\u003cp\u003eThese outcomes encompass life threatening, hospitalization, disability, death, congenital anomaly, required intervention to prevent permanent impairment damage and other adverse events. Among them, the number of adverse reactions associated with progesterone, desogestrel and megestrol was below 30 cases; thus the reference value is significantly limited. Among drugs with over 100 reported adverse reactions, hydroxyprogesterone exhibited the lowest incidence of life threatening (0.7%), while the remaining three progestogens showed minimal variation. Levonorgestrel demonstrated the highest hospitalization rate (32.1%), whereas etonogestrel had the lowest hospitalization rate (9.5%). Although most progestogens have a low mortality rate attributed to depression, medroxyprogesterone displayed a mortality rate of 1.4%, surpassing that of other medications. (table 7).\u003c/p\u003e\n\u003cp\u003e3.4. Hierarchical analysis based on age subgroups\u003c/p\u003e\n\u003cp\u003eLevonorgestrel-related depression showed a positive signal in individuals aged 18-44 and 45-64 across all four algorithms. Etonogestrel-related depression exhibited positive signals in individuals under 18 years old and those aged 18-44, as indicated by ROR, PRR, and IC algorithms; however, EBGM algorithm did not detect any positive signals. \u0026nbsp;Medroxyprogesterone-related depression demonstrated a positive signal in individuals under 18 years old and those aged 18-44 according to all four algorithms. In the age group of 45-64, only the PRR algorithm detected a positive signal while the remaining three algorithms did not show any. Individuals older than 65 years displayed positive signals for hydroxyprogesterone, progesterone, desogestrel, and megestrol based on ROR, PRR, and IC algorithms; however, EBGM algorithm did not indicate any positive signals. (Table 8).\u003c/p\u003e\n\u003cp\u003e3.5.Onset times of Depression\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter the use of progestogen drugs, the time of onset of depression is within 180 days. A lower proportion of depression occurred after 180 days of progestogen use. This suggests that when progestogen drugs are used, the time of onset of depression is mainly within 180 days of medication. However, it is worth noting that a small number of patients still develop depression after 5 years, with medroxyprogesterone having the highest rate (7.7%) (Table 9).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis 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.\u003c/p\u003e \u003cp\u003eA 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[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. 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[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. 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[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. 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[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In addition, several reports suggest that depression or mood swings are one of the important reasons leading to the discontinuation of LNG-IUD[\u003cspan additionalcitationids=\"CR22 CR23 CR24\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, 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[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Another study of 120 premenopausal women using LNG-IUD showed no significant difference in depression scores compared to baseline[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eMedroxyprogesterone 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[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. 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[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. 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[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eAlthough 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[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. 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[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eAdmittedly, 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.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eThe results of this study showed that levonorgestrel, medroxyprogesterone and etonogestrel showed positive pharmacovigilance signals associated with depression. Medroxyprogesterone also showed a positive pharmacovigilance signal associated with suicidal thoughts.We recommend that clinicians monitor for depression-related symptoms when using the aforementioned progestogen. At the same time, due to the small sample size, more clinical studies are needed to confirm the safety of progesterone, desogestrel and megestrol.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eAll data is publicly available on the FDA website (https:// fis. fda. gov/ exten sions/ FPD- QDE- FAERS/ FPD- QDE- FAERS. html).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eHui Gao was responsible for the design of the research, experimental data analysis, and manuscript preparation.Xiaohan Zhai and Yan Hu\u0026nbsp;were\u0026nbsp;responsible for the\u0026nbsp;interpretation of data. Hang Wu was responsible for designed and directed the research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eFunding for\u0026nbsp;this research came from\u0026nbsp;project\u0026nbsp;ZR2022QC167\u0026nbsp;supported by Shandong Provincial Natural Science Foundation and project\u0026nbsp;XY20BS11\u0026nbsp;supported by Heze University doctoral Fundation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eYoung E, Korszun A.Sex, trauma, stress hormones and depression.Mol Psychiatry. 2010 Jan;15(1):23-8.\u003c/li\u003e\n \u003cli\u003eHasin DS, Goodwin RD, Stinson FS, et al. Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry. 2005;62(10):1097\u0026ndash;110\u003c/li\u003e\n \u003cli\u003eWight RG, Sepulveda JE, Aneshensel CS. Depressive symptoms: how do adolescents compare with adults? J Adolesc Health. 2004;34(4):314\u0026ndash;323.\u003c/li\u003e\n \u003cli\u003eChandra A, Martinez GM, Mosher WD, et al. Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth. Vital Health Stat 23. 2005;(25):1\u0026ndash;160.\u003c/li\u003e\n \u003cli\u003eXu S, Wang X, Zhang Y,et,al.Comparison the effects of progestin-primed ovarian stimulation (PPOS) protocol and GnRH-a long protocol in patients with normal ovarian reserve function.Gynecol Endocrinol. 2023 Dec;39(1):2217263.\u003c/li\u003e\n \u003cli\u003eZhang P, Wang G.Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms.Int J Mol Sci. 2023 Apr 10;24(8):6992.\u003c/li\u003e\n \u003cli\u003eShao F, Li Y, Zhao Y.Progestin plus metformin improves outcomes in patients with endometrial hyperplasia and early endometrial cancer more than progestin alone: a meta-analysis.Front Endocrinol (Lausanne). 2023 Jun 21;14:1139858.\u003c/li\u003e\n \u003cli\u003eShufelt CL, Bairey Merz CN. Contraceptive hormone use and cardiovascular disease. 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Depression in midlife women.Maturitas.2016 Dec; 94:149-154.\u003c/li\u003e\n \u003cli\u003eGuillard H, Laurora I, Sober S, et al.Modeling the potential benefit of an over-the-counter progestin-only pill in preventing unintended pregnancies in the U.S.Contraception. 2023 Jan;117:7-12.\u003c/li\u003e\n \u003cli\u003eGuay \u0026Eacute;, Brouillette MJ, Drury J,et al.Rapid Improvement of Post-Partum Depression With Subanesthetic Racemic Ketamine.J Clin Psychopharmacol. 2024 Mar-Apr 01;44(2):196-198.\u003c/li\u003e\n \u003cli\u003eShu Y, Chen J, Ding Y,et al.Adverse events with risankizumab in the real world: postmarketing pharmacovigilance assessment of the FDA adverse event reporting system.Front Immunol. 2023 May 15;14:1169735.\u003c/li\u003e\n \u003cli\u003eBu K, Patel D, Morris R, et al.Dysphagia Risk in Patients Prescribed Rivastigmine: A Systematic Analysis of FDA Adverse Event Reporting System.J Alzheimers Dis. 2022;89(2):721-731.\u003c/li\u003e\n \u003cli\u003eClaire Langlad, Amandine Gouverneur, Pauline Bosco-L\u0026eacute;vy, et al. Adverse events reported for levonorgestrel-releasing IUD Mirena\u0026reg; in France and impact of media coverage.Br J Clin Pharmacol. 2019 Sep;85(9):2126-2133.\u003c/li\u003e\n \u003cli\u003eHoribe M, Hane Y, Abe J,et al. Contraceptives as possible risk factors for postpartum depression: A retrospective study of the food and drug administration adverse event reporting system, 2004-2015.Nurs Open. 2018 Jan 17;5(2):131-138.\u003c/li\u003e\n \u003cli\u003eMichael Cox, John Tripp, Sarah Blacksell.Clinical performance of the levonorgestrel intrauterine system in routine use by the UK Family Planning and Reproductive Health Research Network: 5-year report.J Fam Plann Reprod Health Care. 2002 Apr;28(2):73-7.\u003c/li\u003e\n \u003cli\u003eEisenberg DL, Schreiber CA, Turok DK,et al. Three-year efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system. Contraception.2015;92(1):10\u0026ndash;16.\u003c/li\u003e\n \u003cli\u003eBackman T, Huhtala S, Blom T, Luoto R, Rauramo I,Koskenvuo M. 2000. Length of use and symptoms associated with premature removal of the levonorgestrel intrauterine system: a nation-wide study of 17,360 users. BJOG.2000;107(3):335\u0026ndash;339.\u003c/li\u003e\n \u003cli\u003eCox M, Tripp J, Blacksell S. Clinical performance of the levonorgestrel intrauterine system in routine use by the UK Family Planning and Reproductive Health Research Network:5-year report. J Fam Plann Reprod Health Care.2002;28(2):73\u0026ndash;77.\u003c/li\u003e\n \u003cli\u003eElovainio M, Teperi J, Aalto AM,et al.Depressive symptoms as predictors of discontinuation of treatment of menorrhagia by levonorgestrel-releasing intrauterine system. Int J Behav Med.2007;14(2):70\u0026ndash;75.\u003c/li\u003e\n \u003cli\u003eDaud S, Ewies AA. Levonorgestrel-releasing intrauterine system: why do some women dislike it? Gynecol Endocrinol.2008;24(12):686\u0026ndash;690.\u003c/li\u003e\n \u003cli\u003eHall KS, Steinberg JR, Cwiak CA, et al.Contraception and mental health: a commentary on the evidence and principles for practice. Am J Obstet Gynecol.2015;212(6):740\u0026ndash;746.\u003c/li\u003e\n \u003cli\u003eEnzlin P, Weyers S, Janssens D, et al. Sexual functioning in women using levonorgestrel-releasing intrauterine systems as compared to copper intrauterine devices. J Sex Med.2012; 9(4):1065\u0026ndash;1073.\u003c/li\u003e\n \u003cli\u003eTazegul Pekin A, Secilmis Kerimoglu O, Kebapcilar AG,et al. Depressive symptomatology and quality of life assessment among women using the levonorgestrel-releasing intrauterine system: an observational study. Arch Gynecol Obstet.2014; 290(3):507\u0026ndash;511.\u003c/li\u003e\n \u003cli\u003eWesthoff C, Wieland D, Tiezzi L. Depression in users of depo-medroxyprogesterone acetate. Contraception 1995;51:351\u0026ndash;4.\u003c/li\u003e\n \u003cli\u003eSingata-Madliki M, Hofmeyr GJ, Lawrie TA. The effect of depot medroxyprogesterone acetate on postnatal depression: a randomized controlled trial. J Fam Plann Reprod Health Care 2016:1\u0026ndash;6.\u003c/li\u003e\n \u003cli\u003eMaria Pia Rogines-Velo, Amy E Heberle, Hadine Joffe.Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy.Menopause. 2012 Apr;19(4):471-5.\u003c/li\u003e\n \u003cli\u003eAleknaviciute J, Tulen JHM, De Rijke YB, et al. The levonorgestrel-releasing intrauterine device potentiates stress reactivity. Psychoneuroendocrinology.2017; 80:39\u0026ndash;45\u003c/li\u003e\n \u003cli\u003eFahrenkopf A, Li G, Wood RI,Developmental exposure to the synthetic progestin, 17\u0026alpha;-hydroxyprogesterone caproate, disrupts the mesocortical serotonin pathway and alters impulsive decision-making in rats.Dev Neurobiol. 2021 Sep;81(6):763-773.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 9 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Depression, Progestogen, Pharmacovigilance, Adverse event reporting system, Epidemiology","lastPublishedDoi":"10.21203/rs.3.rs-4639254/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4639254/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eProgestogen commonly used in clinic include levonorgestrel, etonogestrel, medroxyprogesterone, hydroxyprogesterone, progesterone, desogestrel, megestrol. Progestogenare widely used in the treatment of contraception, endometriosis, threatened abortion and other diseases. However, the correlation between progestogenand depression is not clear. Therefore, this study used the FDA Adverse Event Reporting System (FAERS) database to assess the relationship between progestogenand depression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003eIn this study, all data from the first quarter of 2004 to the secondquarter of 2024were extracted and imported into SAS9.4 software for data cleaning and analysis. Report Odds ratio (ROR), Proportional Report ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and Multi-item Gamma Poisson Contraction-machine (MGPS) were used for Bayesian analysis and disproportionation analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eLevonorgestrel, medroxyprogesterone, etonogestrel and desogestrel showed positive signs of depression, and medroxyprogesterone also showed positive signs of major depression. Although none of the progestogenshowed a positive sign for suicide and self-harm, medroxyprogesterone showed a positive sign for suicidal thoughts.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eAnalysis of data from FAERS database showed that levonorgestrel, medroxyprogesterone, etonogestrel, desogestrel were correlated with depression. These findings provide real-world evidence of the potential risk of progestogen-related depression.\u003c/p\u003e","manuscriptTitle":"Pharmacovigilance study of the association between progestogen and depression based on the FDA Adverse Event Reporting System (FAERS)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-29 09:06:45","doi":"10.21203/rs.3.rs-4639254/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-05T07:03:57+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-06T15:23:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"303681085984719349324978726663570008251","date":"2024-09-26T06:31:49+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-19T11:23:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-18T09:59:31+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-07-07T15:45:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-04T04:45:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-06-26T02:02:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b8c8d154-49b3-4ca7-9fe3-7a907160eeae","owner":[],"postedDate":"July 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":35136082,"name":"Biological sciences/Drug discovery/Drug safety"},{"id":35136083,"name":"Health sciences/Health care/Therapeutics"}],"tags":[],"updatedAt":"2025-01-13T16:08:19+00:00","versionOfRecord":{"articleIdentity":"rs-4639254","link":"https://doi.org/10.1038/s41598-025-85826-1","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-01-08 15:58:04","publishedOnDateReadable":"January 8th, 2025"},"versionCreatedAt":"2024-07-29 09:06:45","video":"","vorDoi":"10.1038/s41598-025-85826-1","vorDoiUrl":"https://doi.org/10.1038/s41598-025-85826-1","workflowStages":[]},"version":"v1","identity":"rs-4639254","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4639254","identity":"rs-4639254","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}