The mental health effects of hormonal and hormone-blocking treatments for endometriosis; A systematic review and narrative evidence synthesis

Background Endometriosis affects 1 in 10 females and can cause debilitating pain and subfertility resulting in poor physical and mental health. Management includes surgery and hormonal manipulation (progestins/hormone blockers), many of those off-license. In our tertiary endome- triosis centre many patients fear mental health side effects, or report suffering them with these treatments. Aim We aimed to assess the frequency and severity of mental health side effects from hormonal and hormone- blocking treatments and investigate whether mental health side effects have been adequately studied. 1 Posted on 3 Jul 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.175156697.70025737/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. MethodsPROSPERO registration was performed prior to database searches on Pubmed, OVID, AMED, Embase, Emcare, Ovid MEDLINE(R), Web of Science, PsycINFO, CINAHL, Cochrane Central to identify studies that reported impact on mental health of hormones or hormone-blocking treatments for women with endometriosis. We then systematically searched and synthesised the available evidence. Results466 studies were identified from databases/registers; 464 studies screened, 101 studies sought for retrieval and 101 studies assessed for eligibility, 34 studies were excluded, and 67 studies were included in the review. Of the 67 studies included 42 studies showed an improvement in mental health, 21 studies showed a worsening in mental health and 4 studies did not show any change.

Mental health scores before and after treatment generally showed a significant improvement in depression and anxiety and improved quality of life. However, severe cases of de-novo depression brought on by hormonal endometriosis treatments were reported. A subsect of patients with endometriosis appears to be susceptible to negative mental health side effects.

We can reassure patients that overall hormonal treatments improve mental health, but some individuals will have an intolerance to progestin or hormone-blockers, which can result in a decline in mental health. Adequately powered studies are needed to qualify this effect. Accurate reporting of side effects is mandatory, even for off-license indications.

Endometriosis, Hormonal treatment, mental health, depression, anxiety What is already known on this topic: Few large-scale studies exist of hormonal and hormone-blocking treatments for endometriosis which are po- wered to assess the effect on mental wellbeing. What this study adds: This study is the first to systematically review all available information published on the effects on mental health for patients receiving medical hormonal and anti-hormonal therapies for endometriosis and highlights knowledge gaps. How this study might affect research, practice or policy: Our study provides patients and health care practitioners with current evidence-based information regarding the impact on mental health with these treatments. We call for improved side effect reporting/monitoring for adverse mental health effects by clinicians and adequate design for future studies.

In this study, the terms ’woman’ and ’women’ are used to refer to individuals assigned female at birth who identify as women. However, we recognise and respect that gender identity is personal and diverse, and that not everyone assigned female at birth identifies as a woman. The use of these terms reflects the study’s focus and language, but we acknowledge that gender identity can be fluid and not solely defined by biological sex. Endometriosis is a neuro-inflammatory condition affecting 1 in 10 women of reproductive age[1] equating to 190 million people globally[2]. Endometriosis can cause debilitating pain and subfertility resulting in poor physical, mental and emotional health. The economic burden of this disease is vast, with estimated costs of £1130 to £15,676 per patient per year[3, 4]. Therapeutic approaches comprise of hormonal suppression either for primary disease control or secondary prophylaxis, alongside holistic management strategies, analgesia and surgical interventions. NICE[5] recom- mends hormonal treatments as first-line management of the condition. Progestin based therapies suppress ectopic endometrium-like tissue and thus help reduce inflammation and improve pain symptoms. Progestin 2 Posted on 3 Jul 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.175156697.70025737/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. can be given with or without oestrogen, as injections, tablets or an intra-uterine system. In addition, higher Progestin doses additionally lower oestrogen by supressing ovulation, leading to further endometrial suppres- sion, as do Gonadotrophin Releasing Hormone (GnRH) antagonists or continuous agonists. 30% of women are “dissatisfied”, and 10% “very dissatisfied”, with Progestins either due to lack of efficacy or side effects[6]. Sex steroids however are powerful neurotransmitters, and their manipulation and fluctuations are thought to be a major biological factor causing psychological side effects, such as depression and anxiety[7]. Women are twice as likely as men to develop anxiety and depression[8, 9] and those with endometriosis have been shown to have poorer baseline mental health[10] likely resulting from the complex cause and effect relationship between the depression, anxiety and living with chronic pain. Living with a chronic health condition that has no known cause, no cure, and limited treatment options, compounded by a lack of mental health support, significantly worsens mental well-being[11]. The British National Formulary (BNF) report depressed mood as a “common or very common” side effect of the combined oral contraceptive pill in the average population[12], therefore we would expect this to be at least this amongst patients with endometriosis, if not more prevalent given the known poorer baseline mental health. In our large London-based tertiary endometriosis centre a considerable proportion of endometriosis patients report mental health side effects from hormonal or hormone-blocking treatments, or do not want to try them. This is echoed by our work with focus groups[13]. Furthermore, ‘hormonophobia’, fuelled by social media posts about adverse effects from contraceptive hormo- nes[14] influences whether patients would accept this treatment. Conversely, we also observe in our patients that mental health improves, when pain responds to treatment. We systematically searched and synthesised the available body of evidence to understand how hormonal and hormonal blocking treatment may affect the mental health of women with endometriosis. Understanding that these women may already have adversely impacted mental health, we wanted to determine the frequency and severity of mental health side effects if mental health side effects have been adequately studied to help women make informed evidence-based choices

Asystematicreviewwasperformedusingaprospectivelyregisteredprotocol(PROSPEROCRD42023366826, 25/01/2023). Findings are reported in line with PRISMA guidelines. The search was performed on numerous databases; Pubmed, OVID, AMED, Embase, Emcare, Ovid MEDLINE(R), Web of Science, PsycINFO, CINAHL, Cochrane Central to identify studies that reported impact of hormones and hormone-blocking treatments on mental health for women with endometriosis. Searches commenced from inception to 15th February 2025 without language restrictions and were limited to human studies. An expert patient from the charity Endometriosis-UK co-authored our paper to ensure our narrative review adequately reflected lived experience. We studied changes in mental health in women with endometriosis before and after receiving hormones or hormone-blocking agents, using the PICOS format[15]:Population: Women with endometriosis. Intervention:Hormonal and hormone-blocking treatment. Comparators: Non-hormonal treatment, hormonal or hormone-blocking treatment other than the inter- vention, waiting list controls and placebo or no comparator. Outcomes: Mental health before and after treatment. Study designs: Randomised control trials, non-randomised control trials, cohort studies, cross-sectional studies, cohort series, case reports and before-and-after studies were included. Conference abstracts, letters 3 Posted on 3 Jul 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.175156697.70025737/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. or opinion papers, systematic or non-systematic reviews and meta-analysis were excluded. Papers without methodological details were not included. Search terms were generated to include all terms relating to mental and emotional wellbeing with a focus on depression and anxiety and a list of quality-of-life scoring systems to assess pre and post treatment outcomes by three reviewers (SMS, KM & EB). The search is detailed in supplementary material. A manual search of reference lists of included articles, as well as backward and forward citation tracking, supplemented the database search. When clarification on data was required, authors were also contacted. All references identified by the searches were uploaded into COVIDENCE and de-duplicated. Two reviewers (EB & SMS) screened titles and abstracts separately for eligible articles and two reviewers (SMS & AL) reviewed all full texts of these articles for final study selection. Disagreements were resolved by discussion between reviewers and with a third senior reviewer (EB). Two-reviewers (EB & DM) performed a risk of bias (ROB) assessment using appropriate critical appraisal tools. Disagreements were resolved by discussion and a consensus was reached. The ROB assessment tools used for either type of study design used [16-22] are available in supplementary material. Findings were reported as a qualitative synthesis due to variation in reporting, which precluded meta-analysis.

The initial search identified 466 studies. Two studies were removed as duplicates resulting in 464 studies, which were screened applying the inclusion and exclusion criteria for the study protocol. The PRISMA flowchart can be seen in Table 1. Table 1: PRISMA Flowchart Hosted file image1.emf available at https://authorea.com/users/941590/articles/1311729-the-mental- health-effects-of-hormonal-and-hormone-blocking-treatments-for-endometriosis-a- systematic-review-and-narrative-evidence-synthesis 363 studies were excluded at abstract level as deemed not to answer the research question. 101 studies were then sought for retrieval with assistance from the Royal College of Obstetricians and Gynaecologists (RCOG) Library to obtain full texts. All studies were then assessed for eligibility at full-text level by two independent reviewers(SMSandAL).34studiesoverallwereexcluded;2wrongcomparator,3wrongintervention,5wrong study design, 3 unobtainable in full text, 2 no extractable data, 2 wrong patient population and 17 did not assess mental health when reviewed in more detail. 67 studies were therefore included in the systematic review [6, 23-87] . The included studies, design, hormonal/hormone-blocking treatments evaluated and results from the studies are presented in Table 2. Table2: Characterisationofstudiesandresults.Red=worsenedmentalhealthoutcomes,Green=Improved mental health outcomes, Blue = no change in mental health, Yellow = one treatment improved, and another caused worsening mental health. Studies which showed worsening mental health with hormones and hormone-blocking treatments Author Study design Setting / Country Hormone/s or hormone-blocking agents assessed Study size Timeline of mental/emotional health assessment and time of recorded follow up Scales used to measure mental/emotional wellbeing Interpretation of scale Study results Outcome on mental health with hormones & Risk of Bias (ROB) assessment outcome Were mental health outcomes the primary study outcome? Petta 2005 Randomised Control Trial Multicentre clinical trial/ Brazil GnRH analogue vs. LNG-IUS 82 Baseline and 6 months PGWBI PGWBI: A lower score indicates worse health status Compared to pretreatment values, the PGWBI scores of LNG-IUS users increased by 8.3 (SD ˆ 15) points, whereas the scores of GnRH analogue users increased 6.8 (SD ˆ 18.2) points. This increase was not significant in either group. There was no significant difference between the groups (P = 0.474). Worsened MH with progestin and hormone-blockers (NS) Moderate ROB No (Pain reduction primary outcome) Li 2014 Randomised Control Trial Hospital/ China Two different types of GnRH analogues without add back HRT 280 4 weeks and 9 weeks Adverse side effects were listed and assessed. N/A At 4 weeks and at 9 weeks, statistically significantly more anxiety and depression were found in the triptorelin groups vs. the leuprorelin group. At week 4Anxiety: [Leuprorelin 6 (4.23%)] vs. [Triptorelin 28 (20.29%)] P 0.001.Depression: [Leuprorelin 3 (2.11%)] vs. [triptorelin 38 (27.54%)] P 0.001 At week 9:Anxiety: [Leuprorelin 55 (38.73%)] vs. [Triptorelin 41 (29.71%)] P 0.032Depression: [Leuprorelin 34 (23.94%)] vs. [Triptorelin 44 (31.88%)] P 0.013 Worsened MH with both hormone-blockers; Triptorelin > Leuprorelin (SS) High ROB No (Tolerability of treatment primary outcome) Vercellini 1996 Randomised Control Trial University clinic/ Italy Depot medroxyprogesterone acetate Vs. Oral contraceptive combined with very-low-dose danazol 80 Baseline, 6 months, 12 months Adverse side effects were listed and assessed N/A No statistically significant change in rates of depression between the two groups, however the rate of depression was high in both groups (20% and 18%) there is only one measurement post treatment, no baseline reported. Worsened MH with progestin and CHC. NS between two groups(NS) Moderate ROB No (Tolerability of treatment primary outcome) Zupi 2004 Randomised Control Trial University hospital/ Italy GnRH analogue with add-back HRT vs. GnRH analogue without add-back HRT vs. COCP 133 Baseline, 6 months, 12 months and 18 months. SF-36 (mental health), adverse side effects were listed and assessed SF-36: A lower score indicates worse health status Statistically significant worsening of emotional changes in the patients receiving GnRH without addback vs. GnRH with addback and COCP. No statistically significant changes between groups for mental health.SF-36 mental health domain:GNRH with addback Mental health baseline 58.1 (SD12.3) post treatment 60.5 (SD 14.8) 6-month follow up: 59.2 (SD14.4). GNRH without addback baseline 59.8 (SD12.9) post treatment 60.2 (SD 13.6), 6-month follow up 59.7 (SD 12.90) E+P (similar to COCP) baseline 60.2 (SD 13.6) post treatment 59.4 (SD 11.0), 6-month follow up 59.3 (SD 12.2). Worsened MH with hormone-blockers; GnRH without addback >GnRH with addback and CHC (SS) High ROB No (Pain reduction primary outcome) Ceccaroni 2021 Randomised Control Trial Hospital/ Italy Dienogest vs. GnRH agonists 146 Baseline, 6 months and 30 months Adverse side effects were listed and assessed N/A 43% of patients experienced mood disorders with GnRH analogues, 35.4% experienced mood disorders with Dienogest. No statistically significant differences in mood disorders between the two groups (Dienogest or GnRH analogue). Baseline mood however was not recorded. Worsened MH with progestin and hormone-blockers (NS between groups)High ROB No (Pain reduction primary outcome) Giudice 2022 Randomised Control Trial Community and Hospital/ Africa, Australasia, Europe, North America, and South America GnRH agonist vs. delayed GnRH agonist vs. placebo 1251 Unspecified Adverse side effects were listed and assessed N/A There were nine reports of suicidal ideation across both studies including the run-in period, all in women with a self-reported psychiatric history (placebo run-in [2], placebo [2], relugolix combination therapy [2], and delayed relugolix combination therapy [3]); all patients who had suicidal ideation discontinued study participation. SPIRIT 1: Libido decrease: placebo n = 212, 1 (<1%), GnRH n = 212; 5 (2%), delayed GnRH n = 211; 7 (2%). SPIRIT 2 Libido decrease: placebo n = 204; 4 (2%), GnRH n =206; 11 (5%), delayed GnRh n = 206; 8 (4%). Worsened MH with hormone-blockers (P value not stated)LOW ROB No (Pain reduction primary outcome) Vercellini 2016 Non-Randomised Control Trial Academic department/ Italy Dienogest vs. higher dose oral progesterone (NET) 180 Baseline and 6 months HADS, FSFI HADS: A lower score indicates better health statusFSFI: A lower score indicates worse health status Baseline HADS score for women in the Dienogest group was higher than baseline NET group. Statistically significantly higher HADS score at 6-months follow up (Depression, Anxiety and overall score for Dienogest group vs. NET group). No statistically significant change for FSFI for dienogest vs. NET. Worsened MH with progestins (Dienogest > NET [SS[)Low ROB No (Satisfaction of treatment primary outcome) Oppenheimer 2021 Non-Randomised Control Trial Academic department/ France low dose POP/COCP/Depot provera/Mirena/GnRH Analogues vs. higher dose progestins (Chlormadinone acetate 10mg, Nomegestrol acetate 5mg, Medrogesterone acetate 5mg, Promegestone 0.5mg and Cyproterone acetate 50mg) 214 Baseline and 12 months SAQ-F, EQ-5D SAQ-F: A lower score indicates worse health statusEQ-5D: A lower score indicates worse health status The SAQ score of women exposed to high dose progestins was significantly lower compared to the control group (worsening sexual function in women exposed to high dose progestins), with or without adjustment for covariates (15.5±6.3 vs 18.3±6.2, P=0.03, adjusted effect size -0.44 (95% CI -0.86, -0.02), P=0.04). High-dose progestin intake at T1 was associated with a lower sub-score on two SAQ items: pleasure (1.8±0.8 versus 2.2±0.9, P=0.02), and satisfaction with frequency of intercourse (1.2±1.2 versus 1.8±1.1, P=0.02). The groups did not differ significantly for overall quality of life score (EQ-5D). SAQ score at T0 for High dose progestin 16.4± 4.6, T0 for control 17.0± 5.8, T1 for high dose P4- 15.5±6.3, T1 for control 18.3±6.2 Worsened SF with progestins (SS)Low ROB No (Sexual function primary outcome) 4 Posted on 3 Jul 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.175156697.70025737/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. Studies which showed worsening mental health with hormones and hormone-blocking treatments Lee 2016 Non-Randomised Control Trial Hospital/ South Korea GnRH agonist with add back (leuprorelin acetate 3.75 mg (Leuprin) with 1.0 mg/day of estradiol and 0.5 mg/day of norethisterone acetate. vs. Dienogest 2mg OD 64 Baseline, 3 months and 6 months WHOQOL-BREF (psychological health), MRS WHOQOL- BREF:A lower score indicates worse health statusMRS: A lower score indicates better health status Psychological components of quality-of-life scale and menopausal rating scale score showed no significant difference between the two groups or within the groups with treatment of either GnRH with addback vs. Dienogest. MRS: GnRH + addback group (n=28) at baseline 20.4 +/- 9.2, 3 months 25.1 +/- 10.2, 6 months 25.3+/- 7.8 and Dienogest (n=36) at baseline 22.7 +/-7.2, 3 months 23.9 +/- 8.0 and 6 months 23.7 +/-8.0. No differences were seen between the two groups, at each time point. [Mean +/-SD]. Depression was listed as side effect for 1 patient in GnRh group (3.8 %) and in 4 patients in the Dienogest group (11.1 %). Worsened MH with hormone-blockers and progestins. Progestins worse than hormone-blockers. (NS between the groups).Moderate ROB No (Pain reduction primary outcome) Morotti 2017 Cohort Hospital/ Italy higher dose oral progesterone 103 5 years (nil baseline reported) Adverse effects resulting in discontinuing treatment: Depression N/A 6.8% (7/103) experienced depression Worsened MH with progestins (P value not stated)Low ROB No (Tolerability of treatment primary outcome) Vercellini 2018 Cohort Academic department/ Italy low dose COCP switch to NET vs. NET switch to low dose COCP 67 Baseline and 12 months SF-12 (mental component), HADS anxiety, HADS depression, HADS total, FSFI, Adverse side effects were listed and assessed SF-12: A lower score indicates worse health statusHADS: A lower score indicates better health statusFSFI: A lower score indicates worse health status COCP to NET = 35 and NET to COCP = 32. 1 patient dropped out of the study due to mood changes. Mood changes were reported by 5 (18%) taking COCP who were then switched to NET. After 12-month evaluation 5 (18%) still reported mood changes, therefore not statistically significant difference. When shifting from NET to COCP at baseline 5 (20%) reported mood changes and at 12 months 1 (4%), still not statistically significant as numbers were small. SF-12 mental component OC switched to NET (n=27): baseline 40.0+/-11.7, 12 months 42.6 +/-13.2, NS. SF-12 mental component NET switched to OC (n=25): Baseline 42.1+/- 11.7, 12 months 46.1 +/- 10, NS. HADS TOTAL OC switched to NET (n=27): Baseline 12.4 +/- 8.1, 12 months 11.3 +/-9.1, NS. HADS TOTAL NET switched to COCP (n=25): Baseline 10.1 +/- 7.3, 12 months 7.4 +/- 6.3, p 0.02. FSFI total score OC switching to NET: Baseline 26.2 +/-5.7, 12 months 26.2 +/-6.7, NS. FSFI total score NET switching to COCP: Baseline 21.9 +/- 8.6, 12 months 25.4+/- 7.9, p0.01. After treatment change, good tolerability was reported by 37% of participants who shifted to NETA, and by 52% of those who shifted to OC. At 12-month assessment, 51% of women intolerant to OC were satisfied with NETA, and 65% of those intolerant to NETA were satisfied with OC (intention-to-treat analysis). Other study variables did not vary substantially. Worsened MH with CHC and progestins. CHC > progestins (NS between the groups)Low ROB Yes Chandra 2018 Cohort Hospital/ South Korea Dienogest 2mg OD 203 6 months to 35 months Adverse side effects were listed and assessed N/A 6/182 (3%) experienced depression as a side effect of taking Dienogest. Worsened MH with progestins (p value not given)Low ROB No (Radiological disease volume reduction) Vercellini 2010 Cohort Academic setting/ Italy Vaginal ring ethinyl E 15mcg and 120mcg etonogestrel vs. transdermal 20mcg ethinyl E and 150mcg norelgestromin 207 Baseline and 12 months Adverse side effects were listed and assessed N/A Overall, no significant difference between the ring or the patch with regards to side effects of mood or sexual function changes. Vaginal ring side effect: Depression = 7/116 people (6% total of all those who stopped treatment due to adverse side effects). vs depression with patch 4/116 people (5%). Worsened MH with CHC (NS difference between the groups)Moderate ROB No (Tolerability of treatment primary outcome) Moehner 2020 Cohort Multicentre/ Germany, Switzerland, Russia, Poland, Ukraine, and Hungary Dienogest 2mg OD vs. GnRH-A vs. Danazol vs. COCP, vs. Progestins 26,430 Baseline and undefined follow up Adverse side effects were listed and assessed N/A Overall, 139 (new or worsening) depression cases were confirmed. The IR in DNG users was higher (35.7/10,000 WY; 16 cases) compared to OAED (8.2/10,000 WY; 2 cases) and NAED users (17.0/ 10,000WY; 68 cases). The adjusted HRs were 1.8 (95% CI, 0.3–9.4) for DNG vs OAED and1.5 (95%CI,0.8–2.8) for DNG vs NAED. Although the. results did not allow for a two-fold risk for depression to be excluded, the adjusted HR of 1.5 with an upper 95% confidence limit of 2.8 suggests that it was very unlikely that the relative risk of DNG vs NAED exceeds 3. Worsened MH with progestins and hormone-blockers (p value not given)Low ROB Yes R¨ omer 2018 Cohort Hospital/ Germany Dienogest 2mg OD 37 12 months, 24 months, 36 months, 48 months, and 60 months Adverse side effects were listed and assessed N/A 4/37 (11%) women had depressed mood, none required psychiatric consultation. Worsened MH with progestins (no p value given)Moderate ROB No (Pain reduction primary outcome) La Torre 2024 Cohort Outpatient clinic/ Italy Dienogest 2mg 114 12, 24 and 36 months Adverse side effects were listed and assessed N/A Mood disorders developed in (17.4%) of treated patients who as a result discontinued dienogest. Worsened MH with progestins (p value not given)Moderate ROB No (Tolerability of treatment primary outcome) Jeong 2018 Cross-sectional Outpatient/ South Korea Dienogest treatment immediately following surgery (A), dienogest treatment for a recurrence of endometriosis after surgery (B), or dienogest treatment without any surgery (C). 100 12 months Adverse side effects were listed and assessed N/A Psychological adverse effects after dienogest treatment for one year were assessed: 13/100 reported anxiety, 28/100 depressed and 20/100 nervous. No significant differences between short term use (<12 weeks) and longer-term use (52 weeks). Worsened MH with progestins (no p value)Low ROB Yes Warnock 1997 Case Series Clinical setting/ USA GnRH agonist 4 Unspecified Adverse side effects were listed and assessed N/A 2 patients developed psychosis, one developed panic disorder and major depression with and without psychotic features. Worsened MH with hormone-blockers (p value not given)Low ROB Yes Rachman 1999 Case Report Hospital/ USA GnRH analogue 1 5 months Adverse side effects were listed and assessed N/A After 5 months of GnRH analogues patient developed mania and was admitted to psychiatric unit Worsened MH with hormone-blockers (p value not given)Low ROB Yes Lee 2021 Case report Outpatient clinic/ South Korea Dienogest 2mg OD 1 2 months PHQ-9, BAI, BDI, Adverse side effects were listed and assessed PHQ-9: A lower score indicates better health statusBDI / BAI:A lower score indicates better health status One patient given dienogest post-surgery developed psychosis and suicidal thoughts after 2 months of treatment. She responded to SSRI and after 13 months of treatment the patient was considered stable. Her score on the Patient Health Questionnaire-9 (PHQ-9) was 16 (indicative of severe depression) against a normal score of 4; the Beck Depression Inventory (BDI) score was 43, which also indicated severe depression (the score for mild depression on this scale is 13), and the Beck Anxiety Inventory (BAI) score was 44 indicative of severe anxiety, against a normal score of 5. Worsened MH with progestins (p value not given)Low ROB Yes Studies which showed improved mental health with hormones and hormone-blocking treatments Author Study design Setting / Country Hormone/s or hormone-blocking agents assessed Study size Timeline of mental/emotional health assessment and time of recorded follow up Scales used to measure mental/emotional wellbeing Interpretation of scale Study results Outcome on mental health with hormones? Were mental health outcomes the primary study outcome? El Taha 2021 Randomised Control Trial Hospital/ Lebanon Dienogest vs. COCP: 0.03mg ethinyl estradiol and 3mg drospirenone 70 Baseline and 6 months EHP-30 (emotional domain) EHP-30: A lower score indicates better health status Statistically significant improvement in emotional wellbeing for dienogest group as compared to baseline. Non-statistically significant improvement in the COCP group. Improved mental health with progestin and CHC(SS) Low ROB No (Pain reduction primary outcome) Tanmahasamut 2012 Randomised Control Trial Hospital/ Thailand Surgery + LNG-IUS vs. Surgery alone 55 Baseline, 6 months and 12 months SF-36 (Mental health domain) SF-36: A lower score indicates worse health status SF-36 scores in the treatment group statistically significantly improved from baseline (mental subscale, P.022) and statistically significantly better than those in the expectant management group. Improved mental health with progestin(SS) Low ROB No (Pain reduction primary outcome) SadlerGallagher 2017 Randomised Control Trial Pediatric Gynecology clinic/ USA GnRH analogue with add-back progesterone vs. GnRH analogue with add-back progesterone + oestrogens 50 Baseline, 6 months, 12 months SF-36 (mental health), BDI SF-36: A lower score indicates worse health statusBDI: A lower score indicates better health status Both groups showed statistically significant improvement in mental health. (NA+CEE: +7± 3, p within = 0.015 versus NA: +6± 3, p within = 0.04), although the trajectory of change differed between groups (p between=0.02). There were no significant differences in BDI scores within the groups over time and between the groups. There was not statistically significant change in SF-36 mental health domain between the two groups. Improved mental health with hormone-blockers with add back progestin or CHC.(SS) High ROB Yes Alcalde 2022 Randomised Control Trial Hospital clinic/ Spain COCP containing dienogest in control subjects vs. those with DIE vs. those with DIE and Adenomyosis 42 Baseline and 12 months SF-36 (mental health), SQOL-F SF-36: A lower score indicates worse health statusSQOL-F: A lower score indicates worse health status Statistically significant improvement in mental health and sexual function for those taking COCP containing dienogest but more so for those with DIE or DIE and adenomyosis. Isolated DIE group results:SF36 (mental health)baseline: 33.68 (SD1 0.13), at 12-months follow up: 40.86 (SD 11.20) (statistically significant)SQOL-F Baseline 60.58 (SD 13.28), 12-months follow up: 73.12 (SD 9.82). Improved mental health with CHC(SS) Low ROB Yes Maiorana 2023 Randomised Control Trial Hospital/ Italy Dienogest vs. COCP containing dienogest 64 Baseline and 18 months SF-36 (mental health), EHP-30 (emotional wellbeing), SF-36: A lower score indicates worse health statusEHP-30: A lower score indicates better health status EHP-30 showed statistically significant improvement with both treatment groups in emotional wellbeing F(1, 59)=4.45, p<0.05), SF-36 showed no significant change for mental health domain scores.SF- 36 baseline (T0) comparison between groups: MCS dienogest 36.17 (SD 11.4) Qlaira 40.39 (SD 11.1) NS . T1: dienogest 40.86 (SD 14.59) Qlaira 41.14 (SD 9.78) NS between groups. EHP -30 Emotional wellbeing T0: Dienogest 45.6 (23.6) Qlaira 43.5 (23.8) NS T1 dienogest 30.19 (28.5) Qlaira 26.8 (20.9) NS. Improved EW with CHC and progestin(SS) Low ROB Yes Niakan 2021 Randomised Control Trial Hospital/ Iran Dienogest vs. COCP vs. Placebo 90 Baseline and 3 months WHOQOL- BREF WHOQOL- BREF:A lower score indicates worse health status Greater improvement in psychological wellbeing in the COCP group and the Dienogest group compared with the placebo group, though neither statistically significant in either group. Mean quality of life score (psychological health);Dienogest: Baseline = 17.52 (SD 2.242), 3-month follow up = 20.56 (SD 3.262) NS.COCP Baseline = 18.53 (SD 2.04), 3-month follow up = 21.74 NS (SD 2.982)Placebo: Baseline = 18. 30 (SD 2.200, 3-month follow up = 19.05 (SD 5.3) NS Improved mental health with Progestin and CHC(NS) Low ROB No (Pain reduction primary outcome) Osuga 2021 Randomised Control Trial Multicentre clinics/ Japan Oral GnRH antagonist (10mg vs. 20mg, vs. 40 mg) vs. placebo vs. GnRH analogue injectable 487 Baseline, 3 months and 6 months EHP-30 (Emotional wellbeing) EHP-30: A lower score indicates better health status Equal improvement in emotional wellbeing for those taking GnRH antagonist orally or injectable GnRH analogue when compared with placebo. Highest improvement for the mid and higher dose of GnRH antagonist. baseline: Emotional well-being: 10 mg relugolix 20.7 (20.28); 20 mg relugolix 25.3 (19.72); 40 mg relugolix 21.0 (18.25); Leuprorelin 21.4 (20.08); Placebo 21.9 (20.43). Emotional well-being changes from baseline 3-months: -8.3 (16.44), -8.9 (18.62), -10.4 (17.77), -8.9 (17.34) emotional well-being change from baseline at 6-months: -8.4 (15.92) -15.4 (17.86) -13.3 (16.32) -12.4 (18.33) Improved MH with hormone blockers(p values not presented) Moderate ROB No (Pain reduction primary outcome) Pokrzywinski 2020 Randomised Control Trial Multicentre clinical trial/ 5 continents Placebo (n =374), elagolix 150 mg once daily (n =249), or elagolix 200 mg twice daily (n =248) for 6 months in the EM-I study. The EM-II study enrolled 817 women who were randomly assigned in a ratio of 3:2:2 to receive placebo (n = 360), elagolix 150 mg once daily (n = 226), or elagolix 200 mg twice daily (n = 229) for 6 months. Elaris Endometriosis-I (n = 871) and Elaris Endometriosis-II (n = 815) Baseline, 1 month, 3 months, 6 months EHP-30 (Emotional wellbeing EHP-30: A lower score indicates better health status EM-1 Study: n = 318 LS mean (SE) (n, % meeting threshold). Dysmenorrhea responder at 3 months (n=318) -26.5 (1.1) [201, 63.2%]. Dysmenorrhea non-responder at 3 months (n=408) -11.2 (1.0) [131, 32.1%].EM-2 Study: n=318 LS mean (SE) (n, % meeting threshold). Dysmenorrhea responder at 3 months -21.2 (1.2) [153,51.0%]. Dysmenorrhea non-responder at 3 months (n=396) -12.4 (1.1) [124,31.3%]. Improved MH with hormone-blockers(SS) High ROB No (Pain reduction primary outcome) Guzick 2011 Randomised Control Trial Academic medical centres/ USA Leuprolide 11.25mg IM 3 monthly + addback Norethindrone acetate 5mg OD. vs. COCP (1 mg norethindrone 35 mg ethinyl estradiol) 47 Baseline (40 participants), 1 month, 3 months, 6 months, 9 months, 12 months BDI, ISS BDI: A lower score indicates better health statusISS: A lower score indicates better health status Statistically significant decline in BDI scores from baseline in both groups. There were no significant differences, however, in the extent of reduction in these measures between the groups. The ISS appeared to show improved scores in weeks 24–48 of leuprolide treatment, but there was no overall difference in treatment effect on sexual satisfaction between the two treatments using mixed model analysis. Improved MH with hormone blockers with add-back and CHC(SS; NS between groups) Moderate ROB No (Pain reduction primary outcome) Caruso 2022 Randomised Control Trial University/ Italy COCP (1.5 mg 17b-estradiol (E2) and 2.5 mg nomegestrol acetate (NOMAC) vs. Dienogest 2mg OD 197 Baseline, 3 months, 6 months and 12 months SF-36 (mental score), FSFI, FSDS SF-36: A lower score indicates worse health statusFSFI: A lower score indicates worse health statusFSDS: A lower score indicates worse health status There was a statistically significant improvement in mental scores between baseline and 12 months of treatment for both groups (p<0.001), however there was no difference between the two groups. COCP (n= 99) Baseline 60 +/-7, 3 months 76+/-8, 6 months 84 +/-8, 12 months 88+/-9. Dienogest group (n=98). Baseline 62+/-12, 3 months 75+/-9, 6 months 86 +/-9, 12 months 90 +/-10. FSFI and FSDS scores showed statistically significant improvement within the groups between baseline and 12 months. FSFI showed significant improvement with COCP when compared with Dienogest at 6 p<0.005 and 12 months p<0.006. Improved MH with CHC and progestins (SS; NS between groups) High ROB No (Pain reduction primary outcome) Ozdegirmenci 2011 Randomised Control Trial Women’s health teaching and research hospital/ Turkey Mirena vs. hysterectomy 75 Baseline and 12 months WHOQOL-BREF (Psychological domain) WHOQOL- BREF:A lower score indicates worse health status WHOQOL-BREF (Psychological domain) Mirena coil group 1 (n= 43): z =2.802 p=0.005 . Hysterectomy group 2 (n=32): z=1.455 p=0.146. There was a statistically significant improvement the psychological QOL in the Mirena group pre and post treatment, however there was not significant change in psychological wellbeing pre and post hysterectomy. LNG-IUS seems to have superior effects on psychological and social life. Improved MH with progestins (SS)High ROB Yes Vercellini 2002 Randomised Control Trial Academic centre/ Italy Cyproterone acetate vs. COCP 96 Baseline and 6 months SF-36 (mental health domain), HADS Anxiety, HADS Depression, HADS total, Revised Sabbatsberg Sexual Rating Scale, Adverse side effects were listed and assessed SF-36: A lower score indicates worse health statusHADS: A lower score indicates better health statusSexual Rating Scale:A lower score indicates better health status SF-36 Cyproterone acetate group (n=39) Baseline 55.7+/- 15.6, 6 months 66.1+/-14.7. COCP group (n=36) Baseline 52.7+/-19.5, 6 months 61.3+/-13.9. No significant differences were observed between baseline values in the two study groups. Considerable increases in scores for all dimensions were observed at 6 months in both arms. However, variations were generally greater among participants taking cyproterone acetate. In the oral contraceptive group, differences were significant only for role limitation due to physical (P <.001, Wilcoxon test) and emotional (P <.001) problems, body pain (P <.001), and mental health (P=.01), whereas in the cyproterone acetate group, the differences between baseline and 6-month values were statistically significant for all eight dimensions (P=.03 for social functioning; P <.001 for all others). HADS-TOTAL SCORES: baseline for Cyproterone acetate group (n=39) baseline 13.8 +/-5.8, 6 months 9.5 +/- 7.4. COCP group (n=26) Baseline 14.6+/-6.5. 6 months 10.4+/-4.9. Significant and similar improvements in the Hospital Anxiety and Depression Scale scores were observed in the two study arms (P <.001, Wilcoxon test), and between-group differences were not significant. A significant increase in the Sabbatsberg Sexual Rating Scale scores was observed in both the cyproterone acetate arm and the oral contraceptive arm (P <.001, Wilcoxon test); the groups did not differ significantly. Six patients taking cyproterone acetate and five taking the oral contraceptive reported worsening sexual satisfaction. Three women taking cyproterone acetate and two taking the oral contraceptive reported no sexual activity. Depression was reported in 5 (11%) in cyproterone acetate group vs. 2 (5%) in COCP group. Decreased libido 7 (16%) in crypreterone group vs. 2 (5%) with COCP. Revised Sabbatsberg Sexual Rating Scale (Cryproterone acetate group) baseline = 44.6 +/0 15.8, 6 months 47.4+/- 20.5. COCP Basline 45.8 +/-11.4, 6 months 49.5+/-14.9. Improved MH with progestins and CHC (SS, NS between groups)High ROB No (Tolerability of treatment primary outcome) Carvalho 2018 Randomised Control Trial University teaching hospital/ Brazil ENG-releasing implant vs. LNG-IUS 103 Baseline and 6 months EHP-30 (Emotional wellbeing and sexual wellbeing) EHP-30: A lower score indicates better health status ENG-implant emotional wellbeing (N=51): Baseline 71.6 +/-18.1, 6 month 46.9 +/-20 p<0.0001, LNG-IUS (n=52) emotional wellbeing 58.1 +/- 21.3, 6 months 43.1 +/- 17.2 p <0.0007. Statistically significant improvement in emotional wellbeing with both groups. Sexual intercourse ENG Implant (n=51). Baseline 63.1 +/- 29.9 , 6 months 38.9 +/- 29.6 (P <0.0001). LNG-IUS (n=52) Baseline: 63.5 +/-29.7, 6 months 42.5 +/- 23.6 p <0.0004. Statistically significant improvement in sexual intercourse with both groups. Improved MH with progestins (SS)Moderate ROB No (Pain reduction primary outcome) Zhao 1999 Randomised Control Trial Multicentre clinical trial/ USA Leuprolide vs. Nafarelin 192 3 months, 6 months, 9 months Adverse side effects were listed and assessed N/A Mood swings: Nafarelin at 3 months n=96, 17.8+/-26.4. Leuprolide at 3 months n = 90, 20.5+/-29.7. p = NS. At 6 months; Nafarelin n = 72, 16.7+/-26.7. Leuproline n = 72, 21.6 +/- 32.2. P = NS. 9 months; nafarelin n. =61, 6.9 +/- 11.6, Leuprolide n = 55, 10.6+/-18.7. P = NS. Overall, there was no significant difference in mood swings between the groups however there was improvement in both groups but more significantly in the nafarelin group. Improved MH with both hormone blockers (NS between the groups)High ROB No (Tolerability of treatment primary outcome) Teixeira 2017 Randomised Control Trial Hospital/ Brazil Potentized oestrogen vs. placebo 50 Baseline and 6 months SF-36 (mental health and emotional wellbeing), BDI, BAI SF-36: A lower score indicates worse health statusBDI: A lower score indicates better health statusBAI: A lower score indicates better health status Potentized estrogen group exhibited significant improvement in mental health (MD -14.35; 95% CI -27.58 to -1.12; P = 0.025). Placebo group showed no significant improvement. Depression symptoms (BDI score) showed significant improvement in the potentized estrogen group only (MD 11.53; 95% CI 4.16-18.90; P < 0.001) (Fig. 5). It is worth stressing that this group presented significantly higher score on BDI at baseline compared to placebo group (MD 10.13; 95% CI -18.04 to -2.21; P = 0.004). Anxiety symptoms (BAI score) showed significant improvement in both groups (MD 5.43; 95% CI 2.11-8.74; P = 0.001). Improved MH with Potentized oestrogen (SS)Low ROB No (Pain reduction primary outcome) Strowitzki 2010 Randomised Control Trial Multicentre/ Germany, Italy, and Ukraine Dienogest 2mg PO OD vs. placebo 188 Baseline and 3 months Adverse side effects were listed and assessed, SF-36 SF-36: A lower score indicates worse health status Dienogest patients (n = 102): Depression was seen in 2 patients (2%). Placebo (n = 96); depression n =2 (2.1%), No statistically significant difference between the groups, however both had 2% chance of depression. SF-36 indicated greater improvements in the dienogest group: emotional role (18.4 33.9%, dienogest; 9.6 46.4%, placebo). Mental sum scale and physical sum scale scores showed similar improvements in both groups. Improved MH with progestins (NS)Low ROB No (Pain reduction primary outcome) MehdizadehKashi 2022 Randomised Control Trial Hospital/ Iran Dienogest vs. COCP vs. placebo 89 Baseline and 6 months WHOQOL-BREF (Psychological domain) WHOQOL- BREF:A lower score indicates worse health status Dienogest n =30; Baseline 17.52 +/- 2.242, 6 months 23.19 +/- 3.74, mean difference 5.67 +/- 1.23 P NS. COCP n = 30 baseline 18.53 +/- 2.04, 6 months 23.48 +/- 5.13, mean difference 4.95 +/- 3.08 P NS. Placebo group; n = 29, baseline 18.3 +/- 2.20, 6 months 19.35 +/- 4.61 Mean difference 1.05 +/- 0.43. P NS. (P values reflect comparing before and after intervention). Improvement was observed in the dienogest and the COCP groups for psychological health but not in the placebo group. Improved MH with progestins and CHC (NS) Low ROB No (Pain reduction primary outcome) Miller 2000 Randomised Control Trial Academic site/ USA GnRH agonist (Leuprolide acetate) vs. placebo 120 Baseline, 2 weeks and 4 weeks SF-36 (Mental health) SF-36: A lower score indicates worse health status The baseline mental component t scores showed decreased quality of life for both control and treatment groups. Baseline mental t scores were –0.32± 0.06 for the control group and –0.32± 0.05 for the treated group. s. At 2 weeks the placebo and treated group mental scores were statistically significantly changed from baseline at –0.15± 0.04 (P = .018) and –0.53± 0.05 (P = .003), respectively. These 2-week scores were statistically significantly different between groups (P < .0001). At 4 weeks after injection the placebo group mental score was –0.12± 0.04 and the treated group mental score was –0.58± 0.05. Neither of the 4-week mental component scores were statistically significantly different from the corresponding 2-week score. Improved MH with hormone blockers (SS at 2 weeks post treatment)Low ROB No (Pain reduction primary outcome) Taliberti da Costa Porto 2024 Randomised control trial Hospital/ Brazil Dienogest 2mg vs. LNG-IUS 40 Baseline and 6 months SF-36 (mental health domain) SF-36: A lower score indicates worse health status SF-36 scores (Mental Health domain):DNG group(Mean – SD): baseline 28.8 – 23.3 (p 0.718) and after 6-months treatment 67.8 – 27.8 (0.738)LNG-IUS group(Mean – SD): baseline 26.0-23.3 and after 6-months treatment 63.8-30.9 Improved MH with progestins (SS; NS between groups)Moderate ROB Yes Caruso 2016 Non-Randomised Control Trial Hospital/ Italy COCP (containing dienogest) continuous preparation vs. COCP containing dienogest 21-day regimen 96 Baseline, 3 months and 6 months. SF-36 (mental health), SF-36 (emotional role), FSFI SF-36: A lower score indicates worse health statusFSFI: A lower score indicates worse health status Statistically significant improvement in mental and emotional wellbeing at both 3 and 6 month follow up for continuous regimen. 21/7 regimen had improved mental and emotional scores, but these were not statistically significant at 6 months. FSFI scores were statistically significantly better at 3 and 6 months for the continuous group vs. the 21-day regimen. Improved MH with CHC (SS)Moderate ROB Yes Vercellini 2018 Non-Randomised Control Trial Academic department/ Italy Low dose oral contraceptive (Baseline) vs. Higer dose oral progesterone (intervention) 153 Baseline and 12 months HADS (Depression), HADS (anxiety), FSFI HADS: A lower score indicates better health statusFSFI: A lower score indicates worse health status Statistically significant improvements were observed in HADS (depression), HADS (anxiety) and FSFI at follow up as compared to baseline when patients were taking COC Improved MH with CHC (SS)Low ROB No (Pain reduction primary outcome) Alshehre 2020 Non-Randomised Control Trial University Teaching Hospital/ UK GnRH with add back HRT 27 Baseline and 24 months EHP-30 (mental health domain) EHP-30: A lower score indicates better health status There was a statistically significant improvement in the median EHP-30 (mental health domain) score by 24 months when compared to baseline 8.3 (0–50) and 54.2 (0–100) respectively (Z = 3.301,p < 0.001). This significantly deteriorated after discontinuation of treatment at the 30-month follow up 45.8 (0–70.8) (Z = - 2.51, p = 0.009). Improved MH with hormone-blockers with add-back (SS)Low ROB No (Pain reduction primary outcome) Caruso 2015 Non-Randomised Control Trial University/ Italy Dienogest vs. NSAID (control) 92 Baseline, 3 months and 6 months FSDS, SF-36 mental health domain) SF-36: A lower score indicates worse health statusFSDS: A lower score indicates worse health status SF-36 mental health: Statistically significant improvement in mental health scores for those taking Dienogest after 6 months (p<0.001). Improvement between baseline and 3 months, however this was not statistically significant. Statistically significant improvement in FSDS total score between baseline and 6 months. Baseline: 18.4± 1.3 (n=51), 17.5± 1.8 (n=48) at 3 months and 11.3± 1.4 (n=46) at 6 months. Improved MH with progestins (SS)High ROB Yes Caruso 2020 Non-Randomised Control Trial University/ Italy COC (1.5 mg17b-estradiol (E2) and 2.5 mg nomegestrol acetate 24/4) vs. NSAID 162 Baseline, 3 months and 6 months SF-36, FSFI, FSDS SF-36: A lower score indicates worse health statusFSDS: A lower score indicates worse health statusFSFI: A lower score indicates worse health status Statistically significant improvement in Sf-36 mental health scores for study group (COC) for baseline to 3 months and baseline to 6 months (baseline = 60, 3 months = 76 p<0.001, 6 months = 93) p<0.001. Statistically significant improvement after 6 months in mental scores comparing between study and control group. No statistically significant change in mental health scores for control group (NSAIDs) looking at baseline vs. 3 months vs. 6 months. FSFI score: Baseline = 18.3+/-1.5 (n=99). 3 months = 27.5 +/-1.6 (n=89). 6 months = 30.2 +/-1.8 (77) p<0.001. FSDS score: Baseline =18.5+/-1.5 (n=99). 3 months = (n-89) 13.6 +/-1.7). 6 months= n= 77) 10.2+/-1.8 p<0.001 . Statistically significant improvement in sexual function in study group. Overall statistically significant improvement for control group (NSAID) comparing baseline to 6 months for both FSDS and FSFI. Improved MH with CHC (SS)Moderate ROB No (Pain reduction primary outcome) Bhattacharya 2009 Non-Randomised Control Trial Medical research centre/ India GnRH Triptelin 3.75mg monthly vs. surgical menopause 61 3 months (no baseline) MRS MRS: A lower score indicates better health status Psychological symptoms showed significant difference (Group A (GnRH group) (n=30), 6.46 (3.4 SD); Group B (surgical menopause group), 8.70 (3.1 SD); t = -2.68 p = 0.01. Following surgical menopause, the psychological symptoms are more severe (p = 0.01) than after use of GnRHa. Improved MH with hormone-blockers (SS)High ROB Yes Sukhikh 2021 Non- Randomised Control Trial Twenty gynecology clinics in the Russian Federation/ Russia Dydrogesterone 10 mg 2 or 3 times daily, either between the 5th and 25th days of the menstrual cycle (prolonged cyclical treatment regimen) vs. continuous treatment regimen 350 Baseline, 3 months and 6 months SF-20 (mental health domain), Sexual wellbeing (Likert scale), Adverse side effects were listed and assessed SF-20: A lower score indicates worse health statusSexual wellbeing (Likert scale):A lower score indicates worse health status SF-20 mental health: Cyclical treatment (n=273) 6 months = 18.8 (16.4) P<.0001 vs. baseline/6 months vs. continuous (n=77) = 18.6 (16.1) P<.0001 vs. baseline/6 months. Sexual wellbeing Likert scale: Cyclical treatment (n=273) 6 months = 0.8 (0.9) P<.0001 vs. baseline/6 months vs. continuous (n=77) = 0.9 (1.0) P<.0001 vs. baseline/6 months. 0/273 patients in the cyclical treatment group had to stop treatment early due to adverse reactions, compared with 6/77 patients (7.8%) in the continuous group; Depression n= 1, mood swings n= 1, tearfulness n=1, psychiatric disorders n=2, apathy n=1. Prolonged cyclical and continuous treatment regimens of dydrogesterone therapy both demonstrated a pronounced and similar marked improvements in all study parameters related to quality of life and sexual well-being. Improved MH with progestins (SS)Moderate ROB No (Pain reduction primary outcome) Caruso 2019 Non- Randomised Control Trial University/ Italy Dienogest 2mg OD vs. NSAID 54 Baseline, 3 months, 6 months, 12 months, 18 months and 24 months SF-36 (mental health), FSFI, FSDS SF-36: A lower score indicates worse health statusFSDS: A lower score indicates worse health statusFSFI: A lower score indicates worse health status SF-36 mental health for Dienogest group had a statistically significant (p<0.001) improvement in mental health after 6 months of treatments compared with baseline values, which was maintained up to 24 months of treatment compared with baseline. On the contrary, the women of the control group did not have any Qo change during the study period (p=NS). FSFI for dienogest group: baseline (n=54) 22.3+/- 1.3, 3 months (n=51) 23.9 +/-1.3 (NS), 6 months (n=49) 27.8+/-1.3 (p<0.001), 12 months (n=47) 29.7+/-1.4 (p<0.001), 18 months (n=43) 30.2+/-1.3 (p<0.001), 24 months (n=43) 30.3 +/- 1.7 (p <0.001) by non-parametric Wilcoxon’s rank sum test. FSDS baseline (n=54) 18.4+/-1.3, 3 months (n=51) 17.5 +/- 1.8 (NS), 6 months (n=49) 11.3 +/- 1.4 (p <0.001), 12 months (n=47) 10.1+/-1.6 (P<0.001), 18 months (n-43) 10.3 +/-1.7 (P<0.001), 24 months (n=43) 9.8 +/- 1.5 (p<0.001) by Paired Student’s t -test). From the intergroup statistical comparison at baseline and at the 3rd month follow-up, no difference was observed between the study group and the control group (p= NS), except for dyspareunia (p<0.002). After this, the intergroup difference was statistically significant; in fact, the study group showed an improvement in all FSFI items (p<0.02), in FSFI total score (p<0.001) and in FSDS score (p<0.001), with respect to the control group scores. Improved MH with progestins (SS)High ROB Yes Khashchenko 2023 Cohort Medical Research Centre/ Russia Dienogest 32 Baseline and 12 months BDI, STAI, HADS (Depression), HADS (anxiety), SF-36 (mental health domain) BDI: A lower score indicates better health statusSF-36: A lower score indicates worse health statusHADS: A lower score indicates better health statusSTAI: A lower score indicates better health status Use of Dienogest showed a statistically significant decrease in anxiety/depression scores (BDI, HADS, STAI), and quality-of-life improvement (<0.001) BDI (before therapy) 10.9± 8.9 and (after therapy) 3.8± 3.8 p<0.001, HADS anxiety (before therapy) 6.8± 3.2 and (after therapy) 3.8± 2.1 p<0.001, HADS depression (before therapy) 4.5± 3.2 and (after therapy)1.9± 1.9 p<0.001. Reactive anxiety (STAI-S) * 42.9± 10.6 33.8 ± 8.3, Quality-of-life questionnaire SF-36, Psychological component 52.3± 20.7, 71.0 ± 9.6 Improved MH with progestins (SS)Moderate ROB Yes Barra 2020 Cohort Hospital/ Italy Dienogest 83 Baseline, 6 months, 12 months, 24 months, 36 months. EHP-30 (emotional wellbeing domain) EHP-30: A lower score indicates better health status Statistically significant improvement between baseline and 6 months in emotional wellbeing domain (and overall EHP-30 score). Further statistically significant improvement between 6 months and 12 months and remained stable at 24 and 36 months. side effects reported: Depression 5 (9.6) 6.0. Decrease libido 2 (3.8) Global EHP after 6/12 from 80.7± 7.1 to 74.4± 8.5 points; P < 0.001. After 12 months of treatment, EHP-30 score was further ameliorated in all subdomains in comparison to 6-month follow-up (global score 57.0± 12.1; P < 0.001). Improved MH with progestins (SS)Moderate ROB No (Tolerability of treatment primary outcome) Vercellini 2013 Cohort University/ Italy Highter dose oral progesterone vs. Surgery 154 Baseline, 3 months, 6 months and 12 months HADS (Depression), HADS (Anxiety), FSFI, EHP-30 (Emotional wellbeing domain) HADS: A lower score indicates better health statusEHP-30: A lower score indicates better health statusFSFI: A lower score indicates worse health status Total FSFI scores, anxiety and depression scores and EHP-30 scores improved immediately after surgery, but worsened with time, whereas the effect during progestin use increased more gradually, but progressively, without overall significant difference between-groups at 12-month follow-up. Improved MH with progestins (P value not given)Low ROB No (Satisfaction of treatment primary outcome) Yucel 2018 Cohort Hospital/ Turkey LNG-IUS 45 Baseline, 1 month, 3 month, 6 months, 9 months and 12 months. SF-36 (Mental health) SF-36: A lower score indicates worse health status The mental health scores increased to 44.14± 5.12 from 38.14± 5.59. This effect was especially distinct in patients with a higher preliminary pain score. Statistical significance not reported in the study. Improved MH with progestins (NS)Low ROB No (Pain reduction primary outcome) Techatraisak 2019 Cohort Multicentre/ Thailand, Indonesia, Republic of Korea, Malaysia, Philippines and Singapore Dienogest 444 Baseline and 6 months EHP-30 (Emotional wellbeing) EHP-30: A lower score indicates better health status 61.3% had improvement in emotional wellbeing, 19.6% had a worsening in emotional wellbeing and 18.7% showed no change. In the domain of emotional wellbeing, compared to baseline there was a statistically significant change (emotional well-being; 95%-CI: -17.2;-12.3). Improved MH with progestins (SS)Low ROB No (Pain reduction primary outcome) Yoshino 2022 Cohort Multicentre/ Japan COCP 262 Baseline, 3 months and 6 months MDQ (behavioural effect), EIS, EQ-5D-5L MDQ: A lower score indicates better health statusEIS: A lower score indicates worse health statusEQ-5D-5L: A lower score indicates worse health status Statistically significant improvement in behavioural effect before and during menstruation with use of COCP after 6 months compared with baseline. Statistically significant reduction in mental distress questionnaire with time taking COCP. Statistically significant improvement in EIS (emotional domain) after 6 months. Improved MH with CHC (SS)Moderate ROB Yes Leonardo-Pinto 2017 Cohort University/ Brazil Dienogest 2mg OD 30 Baseline, 6 months and 12 months WHOQOL-BREF (Psychological domain) WHOQOL- BREF:A lower score indicates worse health status Baseline Mean +/- SD 49.25 +/-7.72, 6 months 50.58 +/- 8.27, 12 months 53.75+/- 1.20 p =0.0007. There was a statistically significant improvement in QOL score (psychological domain) for women with DIE treated with Dienogest for 12 months. Improved MH with progestins (SS)Low ROB No (Radiological disease volume reduction) Vercellini 2018 Cohort University/ Italy COCP vs. NET vs. Dienogest vs. surgery 157 Baseline and 12 months SF-12 (mental health), FSFI, Adverse side effects were listed and assessed SF-12: A lower score indicates worse health statusFSFI: A lower score indicates worse health status Baseline SF-12 mental health total score cumulatively for all those on hormonal therapies listed: 41.9 +/-10.5, 12 months follow up 47.0+/-10 (P<0.001). FSFI total score cumulatively for all those on hormonal therapies listed: Baseline 26.4+/-5.6, 12 months 25.3 +/-6.1 (P0.07). Significant improvement in mental health after 12 months of use of hormonal therapies in this study. Marginal non statistically significant worsening of FSFI scores observed after 12 months. Reported side effects with any hormonal treatments given at 3 monthsMood disorders23/151 (15%) at 6 months 22/142 (15%) and 12 months 20/133 (15%).Decreased libidobaseline 3 months 53/151 (35%), 6 months. 51/142 (36%) and 12 months 47/133 (35%). Improved MH with CHC and progestins (SS) but 15% reported mood disorders.Low ROB No (Tolerability of treatment primary outcome) Donnez 2021 Cohort University/ Switzerland Linzagolix 200mg for 12 weeks then 100mg for further 12 weeks 8 Baseline, 3 months and 6 months EHP-30 (emotional wellbeing) EHP-30: A lower score indicates better health status Emotional wellbeing scores EHP 30: Baseline n=8 60.4 (23.5), 3 months (n=8) 9.4 (15.7). Mean change -51.0 (20.9), 6 months 8.3 (15.9) mean change -52.1 (21.2). Improvement in quality of life was demonstrated by marked reduction in all EHP-30 domain scores (emotional well-being) at 12 and 24 weeks Improved MH with hormone-blockers (p Value not given)Low ROB No (Radiological disease volume reduction) 5 Posted on 3 Jul 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.175156697.70025737/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. Studies which showed worsening mental health with hormones and hormone-blocking treatments Grandi 2015 Cohort Outpatient centre of university hospital/ Italy COCP vs. NSAID 34 Baseline and 6 months SF-36 (mental health) SF-36: A lower score indicates worse health status COCP group at baseline SF36 (mental health) = 57.17 +/- 26.31 to 6 months 67.72+/- 19.47; P <0.007) Improved MH with CHC (SS) Low ROB No (Pain reduction primary outcome) Ferrero 2020 Cohort Hospital/ Italy ENG-releasing implant 43 Baseline, 6 months, 12 months and 24 months. EHP-30 (emotional wellbeing) EHP-30: A lower score indicates better health status Baseline 72.8 +/-16.6, 6 months 52.0 +/- 21.5 (P<0.001 compared with baseline), 12 months 49.8 +/-17.3 (P,0.001), 24 months 45.4 +/- 15.5 (p<0.001 compared with baseline and p0.018 compared with 12 months). Overall, there was a statistically significant improvement in emotional wellbeing with the ENG-implant after 6 months and continued throughout the study to 24 months. Improved MH with progestins (SS)Low ROB No (Pain reduction primary outcome) Techatraisak 2022 Cohort Multicentre/ Republic of Korea, Indonesia, Thailand, Malaysia, Philippines and Singapore Dienogest 2mg OD 549 Baseline, 6 month, 24 months EHP-30 (Emotional wellbeing), Adverse side effects were listed and assessed EHP-30: A lower score indicates better health status EHP-30 changes from baseline emotional wellbeing: Baseline n=549, Mean (32.3), SD 25.9. 6 months; n=485, 17.3 mean, 20.3 SD. 24 months - n=98, 9.8 mean, 16.8 SD. Chased from baseline at 6 months = n=484, mean -15, SD 26.7. Change in baseline at month 24 n = 98, mean = -20.6, SD 22.8. Scores for all EHP-30 core and modular instrument scales improved during the first 6 months of dienogest therapy and continued to improve until month 24.Adverse events: Depression was seen in 16 people (1.8%). Improved MH with progestins (SS)Low ROB Yes Sansone 2018 Before and after University/ Italy ENG-implant 25 Baseline, 6 months and 12 months SF-36 (emotional role and mental health), FSFI SF-36: A lower score indicates worse health statusFSFI: A lower score indicates worse health status Etonogestrel implants improve sexual function, and quality of life in patients with ovarian cysts suspected of endometriotic origin. Expressed as median and then (CI). Baseline SF-36: Emotional wellbeing 100 (67.05 - 103.70). 6 months 100 (77.84 - 105.41), 12 months 100 (78.04 - 105.31) NS. Mental health 65 (52.69-71.06), 6 months 67 (55.46 - 74.04) at 12 months 68 (57.1-76.03). P <0.05 vs. baseline and vs. 6 months. Statistically significant improvement in mental health scores from baseline with ENG implant. SFI TOTAL Baseline 24 (21.58-26.89), 6 months 25.35 (22.57 - 28.36) p <0.05 statistically significant improvement in sexual wellbeing compared to baseline, 12 months 26.25 (23.39 - 28.68). p <0.05 statistically significant improvement in sexual wellbeing compared to baseline (not vs. 6 months). Improved MH with progestins (SS)Low ROB Yes Shcherbina 2020 Before and after University/ Ukraine hormone monotherapy progestins, nortestosterone derivatives vs. progestins, nortestosterone derivatives WITH SSRIs and psychotherapy 60 Baseline and 6 months SF-36 (mental health domain), BDI, Spielberger-Hanin test Reactive Anxiety, Personal anxiety SF-36: A lower score indicates worse health statusBDI: A lower score indicates better health status SF-36: Endometriosis patients (n=20) 35.43± 1.0 p <0.05 compared with control group (n=20) at baseline. Mental health was statistically significantly worse in the DIE patients than in the non-DIE patients. BDS DIE patients: Baseline 17.9+/-2.43 (Monotherapy hormonal group), at 6 months 11.51+/-1.66, P<0.05 compared with control group. Baseline for hormones + SSRI group = 16.8+/-1.88 (hormones + SSRI), at 6 months 7.21 +/- 1.25, P<0.05 compared with control group. As a result of treatment there was a statistically significant decrease in depression and anxiety, with women receiving complex therapy (subgroup 2) experiencing pronounced positive dynamics of the studied indicators. The results of the pre-treatment questionnaire indicated lower quality of life scores on the scales of physical and mental health components. Improved MH with progestins and nortestosterone (SS)Low ROB Yes Studies which showed no change in mental health with hormones and hormone-blocking treatments Author Study design Setting / Country Hormone/s or hormone-blocking agents assessed Study size Timeline of mental/emotional health assessment and time of recorded follow up Scales used to measure mental/emotional wellbeing Interpretation of scale Study results Outcome on mental health with hormones? Were mental health outcomes the primary study outcome? Zhao 2013 Randomised Control Trial Multicentre/ China Chinese herbal medicine vs. GnRH agonist (Luperelin or triptorelin) 320 Baseline, 6 months WHOQOL-BREF (Psychological domain) WHOQOL- BREF:A lower score indicates worse health status Chinese medicine (n=136) Baseline psychological 14.3382 +/-1.8361, post treatment 14.74 +/-1.67. p<0.05 compared with pretreatment in same group. GnRH groups (n=141). Baseline psychological 14.4965 +/- 1.8964, post treatment 14.6333 +/- 1.7101. Not statistically significant. Chinese medicine group had statistically significant improvement in psychological wellbeing compared with hormonal treated group who did not have statistically significant improvement, however no significant decrease in psychological wellbeing with GnRH was reported. No statistically significant improvement or worsening of sexual wellbeing with GnRH treatment. No change in MH with hormone-blockers (NS)High ROB Yes Seo 2019 Cohort Hospital/South Korea GNRH agonist + COCP vs. Dienogest after surgery 52 Baseline, 6 months, 12 months, 18 months and 24 months WHOQOL-BREF (Psychological domain) WHOQOL- BREF:A lower score indicates worse health status No difference was found in values of these components at any time point between the two groups. In addition, patterns of change in the psychological domain of the WHOQOL-BREF scores did not differ with GNRH agonist therapy + COCP vs. Dienogest after surgery. No change in MH with hormone-blockers with add back or progestins (NS)Low ROB No (Radiological disease volume reduction) Egekvist 2019 Cohort Hospital/ Denmark Hormonal treatment for endometriosis (COCP, oral progestins, IUS) 80 Baseline, 6 months and 12 months SF-36 (mental health domain), EHP-30 (emotional wellbeing) SF-36: A lower score indicates worse health statusEHP-30: A lower score indicates better health status SF-36: Baseline mental health (n=80) 79.9 (14.4%), 6 months 76.9 (16.3%), 12 months 80.3 (15.1%) p value NS. EHP -30 emotional wellbeing (n=80), baseline 16.2 (19%), 6 months 14.1 (19.2%), 12 months 13.8% (18.3%). p value NS. Overall, there was no statistically significant effect on either mental health or emotional wellbeing for women using hormonal treatments for endometriosis. No change in MH with CHC or progestins (NS)Moderate ROB Yes Biasioli 2023 Cohort Hospital/ Italy COCP + numerous progestins 54 Baseline and 6 months SF-36 (mental health domain) SF-36: A lower score indicates worse health status No statistically significant difference was found in the SF-36 score level (Mental Health Role) No change in MH with CHC or progestins (NS)High ROB Yes Studies which showed worsened mental health with some hormones and hormone-blocking treatments and an improvement with others Author Study design Setting / Country Hormone/s or hormone-blocking agents assessed Study size Timeline of mental/emotional health assessment and time of recorded follow up Scales used to measure mental/emotional wellbeing Interpretation of scale Study results Outcome on mental health with hormones? Were mental health outcomes the primary study outcome? Bergqvist 2001 Randomised Control Trial Hospital/ Sweden Nafarelin vs. MPA 30 Baseline, 6 months and 12 months WHQ (women’s health questionnaire) WHQ: A lower score indicates better health status Baseline anxiety and depression scores; Nafarelin (n=17) 63.9 baseline, 6 months 70.1, 12 months 60.1. MPA (n=13) baseline 65.8, 6 months 63.2, 12 months 54.8. There was a non-significant but perhaps clinically relevant increase in anxiety-depression in the nafarelin group during treatment, which might have been related to a more pronounced decrease in the circulating estradiol level by nafarelin than by MPA. Worsened MH with hormone blockers (NS). Improved MH with progestin (NS).Moderate ROB Yes Of the 67 studies included in the systematic review which assessed mental health outcomes after hormones and/or hormone-blockers, post treatment; 42 studies showed an improvement in mental health, 21 studies showed a worsening in mental health and 4 studies did not show any change. Studies showing improvement in mental health with progestins and combined hormonal con- traception (CHC; progestins and oestrogen) therapies Of the 42 studies which showed an improvement in mental health, 27 used progestin as their hormonal treatment. Nineteen randomised control trials (RCT) showed improvement in mental health and emotional wellbeing scores after treatment with progestin. Eight studies which assessed the impact on mental health of both progestins and CHC showed improved mental health with these treatments. El Taha et al. (2021)[24] performed a RCT (n=70) comparing the effects of Dienogest vs. Combined Oral ContraceptivePill(COCP)giventopatientswithendometriosis. Theyassessedemotionalwellbeingusingthe EHP-30 scale performed at baseline and after 6 months of treatment. They found significant improvement in emotional wellbeing for the dienogest arm compared with baseline scores, with a non-statistically significant improvement in the COCP group. Tanmahasamut (2012)[25] assessed the mental health outcomes for patients undergoing surgical excision of endometriosis alone vs. surgical excision with insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) in an RCT (n=55). The SF-36 (mental health domain) was assessed in patients at baseline, after 6 months and 12 months of treatment. Interestingly, the SF-36 scores with LNG-IUS insertion showed sta- tistically significant improvement from baseline mental health scores (p 0.022) and statistically significantly better scores than those with surgery alone. Maiorana et al. (2023) [30] assessed 64 patients with endometriosis at baseline (T0) and after 18 months (T1) of treatment with either Dienogest (56% patients) or a COCP (44% patients) containing dienogest (Qlaira) using both SF-36 (mental health domains) and EHP-30 (emotional wellbeing). EHP-30 emotional wellbeing scores showed statistically significant improvement in both treatment arms F(1, 59)=4.45, p<0.05, whilst the SF-36 mental health scores showed no significant change. Ozdegirmenci (2011)[38] performed a prospective RCT assessing 75 patients with endometriosis divided into two groups LNG-IUS (n=43) vs. hysterectomy (n-32). Baseline and 12-month post treatment WHOQOL- BREF (psychological domain) scores were assessed z =2.802 p=0.005 and z=1.455 p=0.146 respectively. The LNG-IUS group had superior psychological wellbeing outcomes with statistically significant improve- ment post treatment compared with the hysterectomy group who had no significant change in psychological 6 Posted on 3 Jul 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.175156697.70025737/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. wellbeing pre and post procedure. Studies showing improvement in mental health with hormone-blocking therapies Nine studies showed an improvement in mental health with hormone blocking agents, with or without add back hormone replacement therapy (HRT). Osuga (2021)[33] performed a large RCT with 487 endometriosis patients with a triple-arm study assessing varying doses of oral Gonadotrophin Releasing Hormone (GnRH) antagonist Relugolix (10mg vs. 20mg, vs. 40 mg) vs. placebo vs. GnRH analogue injectable (Leuprorelin). EHP-30 emotional wellbeing scores were assessed at baseline, 3-months and 6-months post treatment. Oral GnRH antagonist and injectable GnRH analogues showed equivocal improvement in emotional wellbeing compared with placebo. The best improvement in emotional wellbeing was demonstrated in the mid and higher dose of GnRH antagonist: Baseline EHP=30 Emotional wellbeing scores: 10 mg Relugolix 20.7 (20.28); 20 mg Relugolix 25.3 (19.72); 40 mg Relugolix 21.0 (18.25); Leuprorelin 21.4 (20.08); Placebo 21.9 (20.43). Emotional wellbeing changes from baseline at 3-months: -8.3 (16.44), -8.9 (18.62), -10.4 (17.77), -8.9 (17.34). Emotional wellbeing changes from baseline at 6-months: -8.4 (15.92) -15.4 (17.86) -13.3 (16.32) -12.4 (18.33). A non-randomised control trial published in 2020 by Alshehre et al.[54] assessed mental health outcomes for endometriosis patients receiving a GnRH analogue Triptorelin SR (11.25 mg) with addback HRT Tibolone (2.5 mg) at baseline and after 24 months of treatment. Alshehre reported a statistically significant improve- ment in the median EHP-30 (mental health domain) score by 24 months when compared to baseline 8.3 (0–50) and 54.2 (0–100) respectively (Z = 3.301, p < 0.001). This however significantly deteriorated after discontinuation of treatment at the 30-month follow up 45.8 (0–70.8) (Z = - 2.51, p = 0.009) showing that mental health improved only for the length of duration whilst receiving treatment. Worsened mental health with hormones and/or hormone-blocking agents Twenty-one studies showed worsening mental health for patients with endometriosis taking hormones or hormone-blocking agents: progestins only (8), progestins and CHCs (3), progestins and hormone-blocking agents (4), hormone-blocking agents only (5), CHC only (1). All studies assessing progesterone therapies involved synthetic progestins, no studies used a micronized progesterone. It is important to highlight that micronized progesterone is associated with fewer side effects than other synthetic progestin therapies due to its ‘bioidentical’ nature, which is thought to cause less of a metabolic impact[88]. The largest study in this group was The Visanne Post-Approval Observational Study (VIPOS) published by Mohener et al in 2020[74]. The study assessed 26,430 people with endometriosis and observed the risk of depression in patients using Dienogest (Visanne) 2mg orally per day; 11.4% used Dienogest (DNG), 12.8% used other approved endometriosis medications (OAED) and 75.7% used hormonal treatments not approved but frequently used for endometriosis treatment (NAED) including progestins and CHCs. There were 139 new or worsening cases of depression in total. The incidence rate in Dienogest users was higher (35.7/10,000 women years; 16 cases) compared to OAED (8.2/10,000 women years; 2 cases) and NAED users (17.0/ 10,000women years; 68 cases). The adjusted hazard ratios were 1.8 (95% CI, 0.3–9.4) for DNG vs OAED and1.5 (95%CI,0.8–2.8) for DNG vs NAED. Overall, the number of depression events were substantially lower than expected. The power of the study was insufficient to exclude risk of newly diagnosed or deteriorating depression for DNG vs OAED or NAED. Whilst a slight increase in depression risk cannot be excluded, this might be explained by baseline severity of endometriosis or unknown country-specific confounding variables. Li et al. (2014)[26] performed a RCT with 280 participants who underwent laparoscopic excision of en- dometriosis and were given one of two GnRH-analogues (Leuprorelin n = 142 or Triptorelin n=138) post operatively. Adverse mental health side effects were assessed and at 4 weeks and at 9 weeks. In both groups, patients developed anxiety and depression however statistically significantly more anxiety and depression were noted in the triptorelin group vs. the leuprorelin group. Anxiety: Leuprorelin 6/142 (4.23%) vs. Trip- torelin 28/138 (20.29%) P 0.001. Depression: Leuprorelin 3/142 (2.11%) vs. triptorelin 38/138 (27.54%) P 0.001. 7 Posted on 3 Jul 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.175156697.70025737/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. Two randomised, double-blinded studies published by Giudice in 2022[47] (SPIRIT 1 and 2 trial) with a total of 1251 participants reported 9 cases of suicidal ideation across both studies subsequently leading to all 9 participants withdrawing from the trial. Relugolix n=5, GnRH-analogue n=2 and placebo n=2. InarecentcohortstudybyLaTorre(2024)[81]17.4%ofthe114participantsusingdienogestforendometriosis developed “mood disorders” subsequently resulting in them having to discontinue the hormonal treatment, with an average time of discontinuation of 7.2 months. Morotti et al. (2017)[61] observed 103 patients with rectovaginal endometriosis receiving an oral Norethin- drone Acetate (NETA) (2.5 mg/day up to 5 mg/day) for 5 years and reported adverse reactions: of the 103 participants (n=7) people developed depression (6.8%). Similar rates of depression were reported by Ver- cellini et al. (2010)[73] with CHCs (Vaginal ring ethinyl E 15mcg and 120mcg etonogestrel vs. transdermal 20mcg ethinyl E and 150mcg norelgestromin) in a study assessing adverse side effects after 12-months of treatment; 6% using the vaginal ring vs. 5% with transdermal CHC patch. There was no statistically signif- icant difference between the two groups (p 0.76). R¨ omer (2018)[77] however reported the rate of depressed mood with Dienogest to be as high as 11% (4/37) in a 5-year retrospective cohort study when assessing the drug’s long-term efficacy and safety in clinical practice. Studies where mental health was the primary outcome investigated The primary outcomes considered in the studies were assessed, 24/67 had mental health changes as the primary outcome. Of the remaining studies, the primary outcomes were reduction in pain (26/67), tolerability of treatment (9/67), satisfaction of treatment (2/67), impact on sexual-wellbeing (1/67) and radiological reduction in endometriosis disease burden (4/67). Fourteen of the 24 studies (58.3%) showed an improvement in mental health with medications, 6/24 (25%) showed worsening of mental health, 2/24 (8/3%) showed no change in mental health with progestins or CHCs, 1/24 (4.2%) study showed no change in mental health with hormone-blockers and 1/24 (4.2%) study showed an improvement in mental health with progestins and worsened mental health with hormone-blockers.

We report that most studies (n=42) observed improvement in mental health with hormonal or hormone- blocking agents for the treatment of endometriosis pain rather than deterioration of mental health (n=21). Thirty-three studies show significant improvement in mental health and overall quality of life with progestins, hormone-blocking agents and CHCs, given our experience of frequent reports of side effects and the high rate of mental health co-morbidity in endometriosis[89]. While many individuals with endometriosis may experience psychological benefits from hormonal downregu- lation, because pain scores improve, some women, outside of their control, are sensitive to hormonal changes, and experience iatrogenic depression and anxiety. These experiences could be influenced by factors such as disease severity, individual coping strategies, and any pre-existing mental health conditions. Patients may prioritise improved physical symptoms over mental health from hormonal downregulating treatments, such as improved pelvic pain at the cost of mental health deterioration. This raises the question of whether managing one aspect of health may inadvertently exacerbate the other, presenting a challenging clinical dilemma. The studies which showed improved mental health outcomes with hormonal or hormone-blocking treatments had either a low (22/42; 52.4%) or moderate (11/42; 26.2%) risk of bias, with 9/42 (21.4%) having a high risk of bias. Six of these 9 studies were RCTs. Similarly, of those studies which reported worsening mental health effects with hormonal or hormone-blocking treatments; 11/21 (52.4%) had low risk of bias, 7/21 (33.3%) had moderate risk of bias and 3/21 (14.2%) had a high risk of bias. The incidence of mental health side effects of hormonal and hormone-blocking treatments may be underre- ported in patients with endometriosis: In research settings: 8 Posted on 3 Jul 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.175156697.70025737/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. • Many researchers fail to define baseline mental health, quantify depression, or adequately power the study for this outcome. • There are published, designed and validated tools to assess side effects[90] but none of the included authors have used them. • Patients who experience adverse mental health effects from prescribed medication often become non- compliant or may drop out of studies. In clinical settings: • Endometriosis patients often have had their symptoms minimized or dismissed by healthcare providers [91] and may not feel empowered to discuss mental health for fear of stigma and clinicians are not routinely screening for this[92] • Patients may feel their concerns about the effects of hormonal treatment on skin or weight are triviali- sed, despite the potential impact on mental health. This can lead to underreporting of such issues, as individuals may fear being perceived as vain or ridiculed. • The high incidence of mental health comorbidity in women endometriosis may need to a normalisation of additional iatrogenic mental health deterioration from treatment by women and clinicians • Many hormones and hormone-blocking treatments are not licenced for the treatment of endometriosis, which could deter women and clinicians from yellow card reporting to the Medicines and Healthcare products Regulatory Agency (MHRA), who encourage reporting of unlicensed and off-license medica- tion side effects.

We can reassure patients with endometriosis that hormonal and hormone-blocking treatments have a bene- ficial impact on mental health in general but warn that there are individuals who may suffer deterioration of mental health, requiring monitoring and reporting to the MHRA. Adequately powered studies, including the correct questionnaires are needed to qualify this effect, and to understand its mechanism. We also need to understand which endometriosis patients are more vulnerable to those side effects and if there is a way of predicting this. It is tempting to speculate that ‘bioidentical’ hormones may result in a better tolerability, and a feasibility study is in preparation to answer this question.

The authors would like to that Professor Khalid Khan for his advice and supervision in the study. COMPETING INTERESTS There are no competing interests to declare. FUNDING There was no fundings for this study. AUTHORS’ STATEMENT The primary author Sophie Michelle Strong (SMS) drafted the manuscript with Elizabeth Ball (EB). Con- ception of the research idea was by EB. Krupa Madhvani (KM), EB and SMS defined the search terms for the systematic review and conducted the initial scoping search. SMS, Amelia Lavington (AL) and Diana Medina (DM) performed abstract screening and full text review with EB as a senior reviewer to assist if any disagreement occurred. EB and DM performed the risk of bias assessment. KM and EB were the seni- or authors who conceived the study and the methodology and edited the manuscript together with Helen Mclaughlin (HM), as an expert patient. SMS, EB, KM, AL and HL reviewed and edited the final version of the manuscript. All authors have approved the version to be published. All authors agree to be accountable for all aspects of the work to ensure that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. 9 Posted on 3 Jul 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.175156697.70025737/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. SUPPLEMENTARY MATERIAL SEARCH TERMS (((endometriosis)OR(adenomyosis))AND((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((hor- monal treatment) OR (GnRH agonist)) OR (GnRH analogue)) OR (Gonadotropin- releasing hormone agonist)) OR (Gonadotropin- releasing hormone analogue)) OR (Gonadotropin releasing hormone agonist)) OR (Gonadotropin releasing hormone analogue)) OR (Goserelin)) OR (Zoladex)) OR (Leuprorelin ace- tate)) OR (Prostap)) OR (Staladex)) OR (Triptorelin)) OR (Decapeptyl)) OR (Gonapeptyl Depot)) OR (Salvacyl)) OR (Buserelin)) OR (leuprolide acetate)) OR (Lupron)) OR (Combined oral contraceptives)) OR (combined pill)) OR (combined oral contraceptive pill)) OR (Ethinylestradiol Desogestrel)) OR (Ethinylestradiol Gestodene)) OR (Ethinylestradiol Drospirenone)) OR (Ethinylestradiol Levonorgestrel)) OR (Ethinylestradiol Norgestimate)) OR (Ethinylestradiol Norethisterone)) OR (Estradiol Nomegestrol acetate)) OR (Estradiol valerate dienogest)) OR (Combined Oral Contraceptives Multiphasic)) OR (Com- bined Oral Contraceptives Monophasic)) OR (Bimizza)) OR (Gedarel)) OR (Mercilon)) OR (Akizza)) OR (Femodette)) OR (Millinette)) OR (Sunya)) OR (Cimizt)) OR (Gedarel)) OR (Marvelon)) OR (Dretine)) OR (Lucette)) OR (Yacella)) OR (Yasmin)) OR (Yiznell)) OR (Akizza)) OR (Femodene)) OR (Katya)) OR (Millinette)) OR (Levest)) OR (Microgynon)) OR (Ovranette)) OR (Rigevidon)) OR (Elevin)) OR (Maexeni)) OR (Cilique)) OR (Lizinna)) OR (Brevinor)) OR (Norimin)) OR (Norinyl-1)) OR (Femodene)) OR (Microgynon)) OR (Zoely)) OR (Logynon)) OR (TriRegol)) OR (Synphase)) OR (Qlaira)) OR (Apri)) OR (Alesse)) OR (Aranelle)) OR (Aviane)) OR (Beyaz)) OR (Desogen)) OR (Estrostep Fe)) OR (Gianvi)) OR (Kariva)) OR (Lessina)) OR (Levlite)) OR (Levora)) OR (Loestrin)) OR (Lybrel)) OR (Lo Ovral)) OR (Nordette)) OR (Ocella)) OR (Low-Ogestrel)) OR (Ortho-Novum)) OR (Previfem)) OR (Reclipsen)) OR (Safyral)) OR (Velivet)) OR (Yaz)) OR (Azurette)) OR (Mircette)) OR (Caziant)) OR (Enpresse)) OR (Ortho Tri-Cyclen)) OR (TriNessa)) OR (Velivet)) OR (Natazia)) OR (Seasonale)) OR (Seasonique)) OR (Lybrel)) OR (Contraceptive Ring)) OR (vaginal ring)) OR (Nuva ring)) OR (Annovera)) OR (progesterone only pill)) OR (progestin only pill)) OR (mini-pill)) OR (Desogestrel)) OR (Lovina)) OR (Hana)) OR (Cerazette)) OR (Norethisterone)) OR (norethindrone)) OR (noriday)) OR (micronor)) OR (Levonor- gestrel)) OR (norgestone)) OR (Dienogest)) OR (Visanne)) OR (Zalkya)) OR (Medroxyprogesterone acetate)) OR (Depot Provera)) OR (Noristerat)) OR (Implanon)) OR (Explanon)) OR (etonogestrel)) OR (Camila)) OR (Errin)) OR (Heather)) OR (Jencycla)) OR (Jolivette)) OR (Nor-QD)) OR (Nora-BE)) OR (Orthoa)) OR (Micronor)) OR (IUS)) OR (IUD)) OR (hormonal coil)) OR (intrauterine system)) OR (intrauterine device)) OR (Mirena)) OR (Kyleena)) OR (Jaydess)) OR (Danazol)) OR (MPA)) OR (medroxyprogesterone acetate)) AND (((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((Beck Depression Inventory) OR (BDI)) OR (Hospital Anxiety and Depression Scale)) OR (HADS)) OR (State- Trait Anxiety Inventory)) OR (STAI)) OR (General Health Questionnaire)) OR (Eysenck Personality Questionnaire)) OR (EPQ)) OR (The Golombok Rust Inventory of Marital State)) OR (Golombok Rust Inventory of Sexual Satisfaction)) OR (GRISS)) OR (The Short-Form McGill Pain Questionnaire)) OR (Symptom Checklist-90-R)) OR (Symptom Checklist-90-Revised)) OR (SCL-90-R)) OR (Depression)) OR (Depressive)) OR (Anxiety)) OR (Bipolar affective disorder)) OR (Mania)) OR (Manic episode)) OR (suicidal ideation)) OR (suicidal attempt)) OR (suicide)) OR (mental health)) OR (Panic attack)) OR (panic disorders)) OR (mood disorder)) OR (psychosis)) OR (psychotic)) OR (psychological side effects)) OR (psychological)) OR (Psychiatric)) OR (State-Trait Anger Expression Inventory-2)) OR (Self-Rating Anxiety Scale)) OR (Self-Rating Depression Scale)) OR (Quality of Life Index)) OR (Hamilton Rating Scale for Depression)) OR (HAM-D)) OR (Hamilton Rating Scale for Anxiety)) OR (HAM-A)) OR (Spielberger STAI)) OR (World Health Organization Quality of Life Assessment-BREF)) OR (WHOQOL-BREF)) OR (Status of health questionnaire)) OR (SF-36)) OR (Hospital Anxiety and Depression Scale-German Version)) OR (HADS-D)) OR (Endometriosis Health Profile)) OR (EHP-30)) OR (The Dutch version of the Female Sexual Function Index)) OR (FSFI)) OR (Short Form-12)) OR (SF-12)) OR (Pain Catastrophizing Scale)) OR (PCS)) OR (Sexual Self-Consciousness Scale)) OR (SSCS)) OR (Toronto Alexithymia Scale)) OR (TAS-20)) OR (Pain Disability Index)) OR (PDI)) OR (Chronic Pain Questionnaire)) OR (CPQ)) OR (Coping Styles Questionnaire)) OR (CSQ)) OR (Courtauld Emotional Control Scale)) OR (CECS))) 10 Posted on 3 Jul 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.175156697.70025737/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. Study design and risk of bias (ROB) assessment tool Study design Reference for ROB assessment tool Cohort studies Critical Appraisal Checklist for Cohort Studies https://jbi.global/critical-appraisal-tools* Non-RCT studies WELLS, G. A., SHEA, B., O’CONNELL, D., PETERSON, J., WELCH, V. & LOSOS, M.The Newcastle-Ottawa Scale (NOS) for assessing The quality of nonrandomized studies in meta-analyses. [Online]. Available from: URL:http://www.ohri.ca/programs/clinical_- epidemiology/oxford.htm. RCT Cochrane ROB 2 https://methods.cochrane.org/bias/resources/rob- 2-revised-cochrane-risk-bias-tool-randomized-trials Cross sectional studies JBI Critical Appraisal Check- list for analytical cross sectional studies https://jbi.global/critical-appraisal-tools Case reports Gagnier JJ, Kienle G, Altman DG, Moher D, Sox H, Riley D, CARE Group. The CARE Guidelines: Consensus-Based Clinical Case Reporting Guideline Development. Headache: The Journal of Head and Face Pain, 2013;53(10):1541-1547. Case series Munn Z, Barker TH, Moola S, Tufanaru C, Stern C, McArthur A, Stephenson M, Aromataris E. Methodological quality of case series studies: an

to the JBI critical appraisal tool. JBI Evidence Synthesis. 2020;18(10):2127-2133 Quasi experimental studies Barker TH, Habibi N, Aromataris E, Stone JC, Leonardi-Bee J, Sears K, et al. The revised JBI critical appraisal tool for the assessment of risk of bias quasi-experimental studies. JBI Evid Synth. 2024;22(3):378-88. *JBI tool excluded high ROB studies, we included high ROB studies, but stating the high ROB

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