{"paper_id":"857a7e5b-2a1f-441b-9c18-adcb33bfc893","body_text":"R E V I E W Open Access\nSafety and efficacy of elagolix (with and\nwithout add-back therapy) for the\ntreatment of heavy menstrual bleeding\nassociated with uterine leiomyomas: a\nsystematic review and meta-analysis\nMustafa Ali 1, Aruna Kumari Hira 2, Haris Jawaid 1*, Faiza Zakaria 1 and Zehra Somjee 1\nAbstract\nBackground: Heavy menstrual bleeding (HMB) is a common clinical finding in patients with uterine leiomyomas\nthat can negatively impact their quality of life. Recently, a novel oral GnRH-antagonist (elagolix) has emerged as a\npossible therapeutic agent for this ailment. Herein data was pooled from clinical trials assessing the safety and\nefficacy of elagolix with and without add-back therapy.\nMain text: PubMed and Cochrane library were systematically searched for RCTs that measured the efficacy and\nsafety of elagolix for the treatment of uterine fibroid-associated HMB. All safety and efficacy endpoints were\ncompared between elagolix-alone, elagolix w/add-back therapy, and placebo. The primary efficacy endpoint was\ndefined as the number of women who achieved menstrual blood loss (MBL) < 80 ml and a reduction in MBL from\nbaseline of > 50% at the end of treatment. Secondary outcomes assessed included change in hemoglobin levels,\nincidence suppression of bleeding and amenorrhea, and the incidence of adverse events. The random effects\nmodel was used to pool data, and heterogeneity was assessed using I 2.\nOur search identified 4 clinical trials meeting our PICO criteria, with a total of 916 patients. Analysis of the primary\noutcome revealed that elagolix-alone was the most effective treatment compared to both placebo (LOR = 3.47, CI\n= 3.03 –3.91, p = 0.000, I 2 = 0.0%) and add-back therapy (LOR = 0.64, CI = 0.12 –1.16, p = 0.016, I 2 = 43.1%).\nFurthermore, both elagolix groups (irrespective of add-back therapy) observed a significant improvement in post-\ntreatment hemoglobin levels as compared to the placebo group (elagolix-alone vs PBO: LOR = 1.44, CI = 0.66 –2.22,\nI2 = 66.0%, p = 0.000; elagolix-w/add-back therapy vs PBO: LOR = 1.22, CI = 0.78 –1.66, I 2 = 0.0%, p = 0.000).\nConcerning safety, while elagolix without add-back therapy had the highest overall incidence of adverse effects\n(elagolix-alone vs placebo LOR = 0.84, CI = 0.48 –1.20, I 2 = 7.8%, p = 0.000; elagolix-alone vs elagolix-w/add-back\nLOR = 0.68, CI = 0.09 –1.26, p = 0.024, I 2 = 64.6%), the incidence of serious (life threatening) adverse events between\nall 3 treatment groups was not statistically different. The inclusion of add-back therapy with elagolix made the\ntreatment noticeably safer (elagolix-w/add-back vs placebo: LOR = 0.19, CI = − 0.10 to 0.48, I 2 = 0.0%, p = 0.194)\nwithout seriously compromising its efficacy.\n© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,\nwhich permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give\nappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if\nchanges were made. The images or other third party material in this article are included in the article's Creative Commons\nlicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons\nlicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain\npermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\n* Correspondence: haris.jawaid1999@gmail.com\n1Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan\nFull list of author information is available at the end of the article\nMiddle East Fertility\nSociety Journal\nAli et al. Middle East Fertility Society Journal           (2021) 26:20 \nhttps://doi.org/10.1186/s43043-021-00064-5\n\nConclusion: High-quality evidence from 4 trials suggests that elagolix is an effective treatment for leiomyoma-\nassociated HMB, with a marked improvement in all efficacy endpoints. Furthermore, the inclusion of add-back\ntherapy in the treatment regimen should be considered as it mitigates the hypoestrogenic effects of elagolix.\nKeywords: Elagolix, Uterine leiomyoma, Heavy menstrual bleeding, Meta-analysis, Add-back therapy\nBackground\nUterine fibroids (leiomyomas) are benign myometrial\nmonoclonal tumors that have been classified as the\nmost common gynecological disorder occurring in\nwomen worldwide [ 1] . By estimation, 70% of women\nb yt h ea g eo f5 0w i l ls h o wt h ep r e s e n c eo fu t e r i n ef i -\nbroids, out of which 30% will be symptomatic. Pa-\ntients with uterine fibroids may also experience a\nplethora of symptoms such as abnormal uterine\nbleeding, pelvic pain, dyspareunia, obstructive effects\non bladder or rectum, and infertility, among others\n[2]. According to a global survey, 59.8% of women\nwith the diagnosis of uterine fibroids self-reported\nheavy and prolonged vaginal bleeding compared to\nthose without fibroids (37.4%) [ 3].\nTreatment and management of this disease varies\nbased on the clinical presentation. Asymptomatic pa-\ntients and those with no intention of conceiving require\nno special treatment and are managed conservatively\nwith periodic monitoring [ 4]. In contrast, symptomatic\npatients may pursue both surgical and pharmacological\navenues. While surgical hysterectomy remains the only\ntrue curative solution, its invasive and highly intensive\nnature bars it from being the first approach. The pre-\nferred approach usually involves either pharmacological\ntherapy such as gonadotropin-releasing hormone ago-\nnists and antagonists, or selective progesterone receptor\nmodulators (SPRMs), or surgical options such myomec-\ntomy and laparoscopic techniques (such as mini-\nlaparotomy-assisted vaginal surgery) [ 5, 6].\nWhile numerous different pharmacological approaches\nto treating uterine fibroids are available, the current\nfore-runners with the strongest evidence-base include\nGnRH agonists and SPRMs [ 6]. Moreover, it is not un-\ncommon in such cases to include add-back therapy of\nsome sort (estrogen, progesterone, or a combination of\nboth) in the therapeutic regimen so as to offset the\nhypoestrogenic effects of these drugs [ 7].\nRecently, a novel GnRH antagonist (elagolix) has gar-\nnered attention with its potential role as an oral treat-\nment option for HMB associated with uterine fibroids\nhaving become an area of interest. The role of elagolix\nfor the treatment of endometriosis-related pain has been\nunequivocally proven and cemented by previous studies\n[8, 9], notably Ezzati et al. [8]. However, major clinical\ntrials evaluating its efficacy and safety for management\nof heavy menstrual bleeding in leiomyoma patients have\nonly concluded relatively recently, with a few that are\nstill underway ( NCT03886220, NCT03271489)[ 10, 11].\nRecently, the results from two phase 3 trials have been\npublished, shedding new light on elagolix as a potential\ntreatment for uterine fibroid-associated menorrhagia,\nand necessitating an evaluation of both its efficacy and\nsafety in this context. The primary focus of this study\nwould be to undertake a careful analysis of all evidence\navailable, both new and old, in order to reach a consen-\nsus as to the role of elagolix with and without add-back\ntherapy in reducing heavy menstrual bleeding in patients\nas the primary endpoint. Other safety and efficacy out-\ncomes including its impact on the menstrual cycle\n(amenorrhea or suppression of bleeding), effect on\nhemoglobin levels, and any adverse effects during the\ncourse of treatment will also be evaluated as secondary\nendpoints.\nAccording to a study, 24% of women considered the\ndebilitating effects of uterine fibroids a major factor be-\nhind failed career ambition [ 12]. Specifically, HMB in\nwomen was revealed to profoundly impact their daily\nquality of life, preventing them from fully engaging in\nfamily, professional, and social activities [ 13]. In addition\nto lower productivity, and affecting their school and\nwork, it may also lead to long-term health consequences\nsuch as anemia due to iron deficiency [ 14]. It is evident\nthat uterine fibroids contribute to a massive economic\nburden for women as well as healthcare systems. Results\nof this meta-analysis may assist healthcare professionals\nreach another safe and cost-effective option with the po-\ntential to be at the forefront of medical management for\nthis disease, thereby earning the affected women a well-\ndeserved respite.\nMain text\nMethodology\nRandomized clinical trials were selected for this review\nand meta-analysis, based on the PICO criteria described\nas follows. The population of the study included non-\npregnant, premenopausal adult females diagnosed with\nuterine leiomyoma complaining of heavy menstrual\nbleeding (menstrual blood loss> 80 ml during at least 2\nconsecutive menstrual cycles). Patients in the interven-\ntion group received elagolix with or without add-back\ntherapy, while the control group was only given placebo.\nThe primary outcome assessed was the number of\nwomen without heavy menstrual bleeding at the end of\nAli et al. Middle East Fertility Society Journal           (2021) 26:20 Page 2 of 12\n\ntreatment. Additionally, multiple secondary endpoints\nincluding suppression of bleeding (spotting allowed),\namenorrhea (no spotting allowed), changes in\nhemoglobin levels, and serious and total adverse events\nwere also assessed.\nA comprehensive literature search of PubMed, PMC\ncentral, Cochrane Library, and Google Scholar was con-\nducted by 2 independent reviewers using a search string\ncomposed of the following key-terms: “Elagolix,”“ ori-\nlissa,”“ menstrual bleeding, ”“ menorrhagia,”“ fibroids,”\nand “leiomyoma.” All studies published from January,\n2000, to 1 January, 2021 (date of last search), with full\ntexts available in English were considered for analysis.\nReviewers screened studies by title and abstract, and the\nfull-text article was referred to where more information\nwas needed. In the event of any disagreements, a third\nreviewer was consulted. Relevant data was extracted\nfrom the selected studies using piloted forms by 2 inde-\npendent reviewers and was stored electronically in a\nspreadsheet. This extracted information included year of\nstudy, lead author/trial name, design, inclusion/exclusion\ncriteria, population demographics and baseline clinical\ncharacteristics, details of interventions and controls in-\ncluding dosages, duration of treatment, the outcomes of\ninterest described above including their respective\nfollow-up periods, and any funding sources. Studies were\nincluded in the systematic review and meta-analysis if\nthey were RCTs and met the PICO criteria described\nabove. In case of multi-armed trials with different dos-\nages of elagolix, only those arms with 600 mg/day were\nincluded in the analysis as they were consistently re-\nported by all included studies. Similarly concerning add-\nback therapy, only regiments including 1.0 mg estradiol\nwere included to allow for a fair pooling of results. A\nPRISMA flow diagram was used to illustrate the search\nstrategy results [ 15].\nRisk of bias in individual studies was assessed using\nthe Cochrane Risk of Bias Tool for parallel, independent\nrandomized clinical trials (CRoB Tool) [ 16].\nDirect pairwise meta-analysis was used to pool data\nfrom these studies using the Mantel-Haenszel random\neffects model. Log-odds ratio (LOR) with 95% confi-\ndence intervals was the chosen effect estimate, and het-\nerogeneity was reported as I 2. Forest plots were\nconstructed to visualize the differences in outcomes be-\ntween the 2 interventions and placebo. Funnel plots\nwere constructed and Harbord ’s test was performed to\nstatistically assess any publication bias. Leave one out\nsensitivity analysis was also conducted to ensure that a\nsingle study was not driving the results.\nResults\nOur search strategy identified 3 publications [ 17–19],\nreporting results from 4 multi-armed randomized\ncontrolled trials that met our criteria for inclusion in the\nreview (Fig. 1). Data from a total of five arms (from the\n4RCTs) which met the previously described PICO cri-\nteria were included in the meta-analysis.\nThe basic study characteristics and the outcomes\nassessed by the included trials are shown in Tables 1\nand 2 respectively. Table 3 shows the basic demograph-\nics and baseline clinical characteristics of study partici-\npants. It is evident that while there is no notable\nvariation in the participant ages between the trials, the\nBMI of patients in Elaris UF-1 and UF-2 is higher com-\npared to the other studies. Both of these patient charac-\nteristics, however, are similar between treatment groups\nin all trials. Additionally, patient hemoglobin levels, and\nbaseline menstrual blood loss, are observed to be similar\nbetween all treatment groups and studies. While the\nsame is generally true for uterine volume, there is a not-\nable exception (Carr 300). Uterine volumes in this case\nare generally higher than in other trials, and significant\nwithin-group variation can also be appreciated.\nResults of quality assessment of individual studies con-\nducted using the CRoB tool are shown in Table 4. Both\nphase 3 trials and the phase 2b study were evaluated to\nhave an overall low risk of bias. There were some con-\ncerns regarding the phase 2a trial as there was insuffi-\ncient information to make an assessment regarding\nrandomization, blinding, and allocation concealment.\nWith respect to the primary outcome (number of\nwomen with menstrual blood loss < 80 ml and a reduc-\ntion of > 50% from baseline), the pooled analysis re-\nvealed that elagolix without add-back was significantly\nmore effective as compared to both placebo (LOR =\n3.47, CI = 3.03 –3.91, p = 0.000, I 2 = 0.0%) and add-back\n(LOR = 0.64, CI = 0.12 –1.16, p = 0.016, I 2 = 43.1%)\n(Fig. 2). Moreover, elagolix with add-back therapy while\nnot as effective as elagolix alone was still significantly\nbetter when compared to placebo (LOR = 2.74, CI =\n2.21–3.27, I2 = 48.0%, p = 0.000). This same trend of ela-\ngolix being the most effective, followed by add-back\ntherapy, was also observed in all secondary bleeding end-\npoints. Concerning suppression of bleeding, elagolix was\nmore effective than both placebo (LOR = 4.61, CI =\n3.96–5.27, I 2 = 0.0%, p = 0.000) and add-back (LOR =\n1.50, CI = 1.17 –1.83, I 2 = 0.0%, p = 0.000) (Fig. 3a). The\nsame was also true regarding placebo (LOR = 4.51, CI =\n3.82–5.20, I 2 = 0.0%, p = 0.000) and add-back (LOR =\n1.45, CI = 1.12 –1.78, I 2 = 0.0%, p = 0.000) therapy in\namenorrhea (Fig. 3b).\nPatients in the phase 2 trials who were given elagolix\nwere observed to have had significant improvement (> 1\nmg/dL increase) in their hemoglobin levels compared to\nthe placebo group (elagolix alone vs PBO: LOR = 1.44,\nCI = 0.6 –2.22, I 2 = 66.0%, p = 0.000; elagolix w/ add-\nback therapy vs PBO: LOR = 1.22, CI = 0.78 –1.66, I 2 =\nAli et al. Middle East Fertility Society Journal           (2021) 26:20 Page 3 of 12\n\n0.0%, p = 0.000) (Fig. 4). Interestingly, this outcome did\nnot differ significantly between patients given add back\ntherapy and those given elagolix alone (elagolix alone vs\nelagolix w/add-back therapy: LOR = 0.21, CI = − 0.59 to\n1.01, I 2 = 68.2, p = 0.607). While the phase 3 trials in-\nstead reported the number of women with both baseline\nhemoglobin ≤10.5 g/dL and who observed an increase of\n≥ 2 g/dL, these results were similar to those from the\naforementioned studies. There was significant variation\nwith this respect to this outcome between the three\ntreatment groups (UF1: p < 0.001; UF2: p < 0.02). How-\never, it can be inferred that this outcome did not vary\nsignificantly between elagolix alone and elagolix with\nadd-back therapy (UF-1: elagolix alone difference from\nPBO = 49.7%, CI = 30.27 –69.18, elagolix w/ add-back\ntherapy difference from PBO =45.4%, CI = 26.9 –63.92;\nUF-2: elagolix alone difference from PBO = 19.2%, CI =\n− 6.0 to 44.3, elagolix w/ add-back therapy difference\nfrom PBO =29.2%, CI = 7.6 –50.7).\nWith reference to serious adverse events (life-threaten-\ning complications that resulted in discontinuation of\ntreatment), neither group varied significantly as com-\npared to the other two (Fig. 5). On the other hand when\ncomparing overall adverse effects, no significant differ-\nence was found between patients receiving placebo and\nadd-back therapy (LOR = 0.19 CI = − 0.10 to 0.48 I2 =\n0.0%, p = 0.194). In contrast patients receiving elagolix\nexperienced a higher incidence of adverse events than\nboth placebo (LOR = 0.84 CI = 0.48 –1.20 I 2 = 7.8% p =\n0.000) and add-back (LOR = 0.68, CI = 0.09 –1.26, p =\n0.024, I 2 = 64.6%) (Fig. 6). Further analysis revealed that\nhot flashes, nausea, and headaches were the only re-\nported adverse effects that varied in incidence based on\nthe treatment (Fig. 7, Supplemental Figures 1-3). Hot\nflashes were reportedly higher in the elagolix only treat-\nment group compared to both placebo (LOR = 2.81, CI\n= 2.34 –3.29, p = 0.00, I 2 = 0.0%) and add-back groups\n(LOR = 1.66, CI = 1.29 –2.03, p = 0.0, I 2 = 22.8%). On\nthe other hand, nausea was significantly higher in the\nadd back group compared to the elagolix only group\n(LOR = 0.77 CI = 0.30 –1.24, p = 0.001, I 2 = 0.0%). Fur-\nthermore, the incidence of headaches was significantly\nlower in the placebo group when compared to both the\ninterventions (E vs PBO: LOR = 0.75, CI = 0.28 –1.21, p\n= 0.002, I 2 = 0.0% ; EA vs PBO: LOR = 0.48, CI = 0.02 –\n0.94, p = 0.042, I2 = 0.0%).\nFig. 1 PRISMA diagram\nAli et al. Middle East Fertility Society Journal           (2021) 26:20 Page 4 of 12\n\nAnalysis of the risk of bias across studies concerning\nthe primary outcome revealed no significant publication\nbias as evidenced by the funnel plot and results of the\nharbord-egger test (Supplemental Figure 4). Addition-\nally, leave one out sensitivity analysis showed that the\npooled result for the primary outcome did not vary\nsignificantly with the exclusion of any specific study\nfrom the analysis (Supplemental Figures 5-7).\nDiscussion\nAs discussed, while elagolix is a well-established treat-\nment option for pain associated with endometriosis [ 20];\nTable 1 Basic study characteristics\nStudy Study design Duration of\ntreatment/\nfollow-up\nCountry Population Intervention\nArcher et al.\n(NCT01441635)\nPhase 2a, dose-ranging,\nmultiple-cohort study\n- 3-month\ntreatment\n- 3-month\nfollow-up\nUSA (including\nPuerto Rico)\nPBO = 50\nElagolix\n100 BD =\n33\nElagolix\n200 BD =\n35\nElagolix\n300 BD =\n30\nElagolix\n400 QD =\n32\nElagolix\n600 QD =\n30\nE200 +\n0.5E2/\n0.1NETA =\n34\nE300 + CEP\n=2 6\nElagolix only = Elagolix 100 mg BD; Elagolix 200 mg\nBD; Elagolix 300 mg BD; Elagolix 400 mg QD; Elagolix\n600 mg QD; Elagolix +ABT = Elagolix 300 mg + CEP\n(continuous low-dose 1.0 mg E2 continuously and\ncyclical oral Progesterone 200 mg); Elagolix 200 mg\nBD + 0.5 mg E2/0.1 mg NETA\nCarr et al.\n(NCT01817530)\nPhase 2b, double-blind,\nrandomized, placebo-\ncontrolled, parallel-group\nstudy\n- 6-month\ntreatment\n- 6-month\nfollow-up\nUnited States\n(including Puerto\nRico), Canada,\nChile,\nand the United\nKingdom\nPBO = 65\nElagolix\nonly = 65\nElagolix +\n0.5E2/\n0.1NETA =\n64\nElagolix +\n1.0E2/\n0.5NETA =\n65\nPlacebo\nElagolix only = Elagolix 300 mg BD; Elagolix + ABT =\nElagolix 300 mg + 0.5 mg E2/0.1 mg NETA; Elagolix\n300 mg + 1.0 mg E2/0.5 mg NETA\nPBO = 78\nElagolix\nonly = 77\nElagolix +\n0.5E2/\n0.1NETA =\n76\nElagolix +\n1.0E2/\n0.5NETA =\n77\nPlacebo\nElagolix only = Elagolix 600 mg QD; Elagolix + ABT =\nElagolix 600 mg + 1.0 mg E2/0.5 mg NETA; Elagolix +\nABT = Elagolix 600 mg + 0.5 mg E2/0.1 mg NETA\nElaris UF-1\n(NCT02654054)\nPhase 3, double-blind, ran-\ndomized, placebo-\ncontrolled\n- 6-month\ntreatment\n- 12-month\nfollow-up\nUnited States\n(including Puerto\nRico)\nPBO = 102\nElagolix\nonly = 104\nElagolix +\nABT = 206\nPlacebo\nElagolix only = Elagolix 300 mg BD; Elagolix + ABT =\nElagolix 300 mg + 1.0 mg E2/0.5 mg NETA\nElaris UF-2\n(NCT02691494)\nPhase 3, double-blind, ran-\ndomized, placebo-\ncontrolled\n- 6-month\ntreatment\n- 12-month\nfollow-up\nUSA (including\nPuerto Rico) and\nCanada\nPBO = 94\nElagolix\nonly = 95\nElagolix +\nABT = 189\nPlacebo\nElagolix only = Elagolix 300 mg BD; Elagolix + ABT =\nElagolix 300 mg + 1.0 mg E2/0.5 mg NETA\nE2/NETA E2 (estradiol) with norethindrone acetate\nAli et al. Middle East Fertility Society Journal           (2021) 26:20 Page 5 of 12\n\nits use for the treatment of HMB is a novel idea, with all\nclinical trials having been conducted in the past 3 years.\nThis meta-analysis summarizes the results of 4 random-\nized control trials encompassing a total of 916 patients,\nevaluating the efficacy and safety of elagolix and elagolix\nwith add-back as compared to placebo for the treatment\nof HMB in patients with uterine fibroids.\nThe results of our meta-analysis found a signifi-\ncantly positive correlation between the administration\nof elagolix (both with or without add back therapy)\nand the achievement of the primary study endpoint\n(reduction of menstrual blood volume to < 80 ml per\nmonth and a greater than 50% decrease from base-\nline). The inclusion of add-back therapy in the treat-\nment regimen resulted in a decrease (LOR = 0.64, CI\n=0 . 1 2–1.16) in the number of patients who achieved\nthe primary outcome, However, elagolix even with\nadd-back therapy was a significant improvement over\nplacebo. These findings are consistent with the results\nof each individual trial and suggest that elagolix with-\nout add-back therapy is the most effective manage-\nment for heavy menstrual bleeding in patients of\nuterine leiomyomas. The heterogeneity for each pair-\nwise comparison was acceptable (I 2 < 50%, p >0 . 1 ) ,\nthereby lending credence to these findings. Further-\nmore, the evidence from the trials was evaluated to\nbe of high quality (Table 4), which in conjunction\nwith the lack of publication bias (figure S 4) speaks to\nthe strength and validity of this and all subsequent\nanalysis.\nElagolix is a non-peptide oral gonadotropin-\nreleasing hormone (GnRH) antagonist which competi-\ntively inhibits the GnRH receptors in the pituitary\ngland [ 21]. Its oral administration was reported by\nprevious research to quickly suppress LH levels in a\ndose dependent manner; this effect being less promin-\nent for FSH [ 22]. This in turn decreases the produc-\ntion of the main ovarian hormones: estrogen and\nprogesterone [ 23]. A conclusion was therefore reached\nthat elagolix allows for modulation of gonadotropin\nand ovarian hormone concentrations, with a partial\nsuppression at lower doses and nearly full suppression\nat higher ones [ 20, 21]. Thus by suppressing\npituitary-ovarian axis, elagolix (a GnRH antagonist)\nTable 2 Outcomes assessed\nEfficacy combined Safety combined\nPrimary endpoints:\n1. Percentage of women who had menstrual blood loss volume of less than\n80 mL at the final month and a 50% or greater reduction in menstrual\nblood loss volume from baseline to the final month.\n2. Mean and percentage change in MBL from baseline to last complete\ntreatment cycle (last 28 days)\n3. Percentage of bleeding days\n4. Percentage of women with suppression of bleeding and amenorrhea\n5. Posttreatment return to menses\n6. Changes in hemoglobin concentrations\nSecondary endpoints:\n1. Change from baseline in the volume of the fibroid and the uterus (both\nassessed using ultrasound evaluation)\n2. Change from baseline in Uterine Fibroid Symptom Quality of Life (UFS-\nQoL) questionnaire scores\n3. The number of bleeding days*\n4. Patient Global Impression of Change (PGIC) questionnaire for menstrual\nbleeding and non-bleeding uterine fibroid symptoms*\n5. Change and percent change from baseline in fibroid and uterine volume\n6. Change from baseline for the EuroQoL-5D (EQ-5D-5L)*\n7. The Health Care Resource Utilization (HCRU) questionnaire*\n8. Change from baseline for the WPAI*\n1. Incidence and severity of adverse events (AEs), including AEs of\nspecial interest (e.g., hypoestrogenic AEs; osteoporosis and osteopenia;\nanaphylactic reaction; severe cutaneous adverse reactions and drug-\ninduced rash; depression and suicide or self-injury)\n2. Clinical laboratory assessments, including lipid panel\n3. Clinically meaningful changes in ultrasound evaluation (e.g., ovarian\ncysts)\n4. Bone mineral density. α*\n5. Relationship to the study drug (reasonable possibility or no\nreasonable possibility)α*\n*ULF-1/2 only, αCarr et al. only\nTable 3 Study demographics and baseline clinical characteristics\nStudy NCT no. Elagolix\ndosage\nAge\n(mean years)\nBMI* Menstrual blood\nloss/ ml\nHemoglobin\nlevels/ gdL-1\nUterine volume\n/cm3\nArcher NCT01441635 300 BD 41.6/42.6/41.6 28.3/29.0/29.6 334/206/266 11.0/11.3/10.3 490/576/659\nCarr NCT01817530 300 BD 44.0/43.0/44.0 30.0/30.0/30.0 238/265/296 11.1/10.5/10.4 627/680/816\n600 QD 43.0/42.0/43.0 30.7/31.0/31.0 222/208/247 10.9/10.7/11.0 570/577/582\nElaris UF-1 NCT02654054 300 BD 41.6/42.6/42.6 33.8/33.4/33.3 255/249/238 11.0/10.6/11.1 478/500/475\nElaris UF-2 NCT02691494 300 BD 42.5/42.2/42.5 33.8/34.5/33.2 254/225/229 11.0/11.0/11.1 550/537/496\nData is displayed as placebo/elagolix only/elagolix with add-back\nAli et al. Middle East Fertility Society Journal           (2021) 26:20 Page 6 of 12\n\ncan significantly decrease the size of uterine leiomyo-\nmas, leading to a subsequent decrease in heavy men-\nstrual bleeding [ 24].\nWith respect to our secondary bleeding end points\nof suppression of bleeding and amenorrhea, elagolix\nalone was shown significantly more likely to lead to\nboth outcomes when compared to either the placebo\nor the EA groups. A possible explanation for this is\nprovided once more, by its anti-GnRH action.\nOversuppression of the ovarian hormones brought on\nby elagolix is likely to disrupt the normal menstrual\ncycle, leading to the observed amenorrhea and sup-\npression of bleeding.\nWhen considering the patient hemoglobin levels,\npooled analysis of the phase 2 trials reported a posi-\ntive correlation between the use of elagolix and the\npercentage of women who had observed an increase\nof ≥ 1 g/dl in hemoglobin levels. The heterogeneity in\nTable 4 Risk of bias analysis\nCochrane Risk of Bias Review for RCTs\nStudy Random sequence\ngeneration\nAllocation\nconcealment\nBlinding of\npersonnel\nBlinding of outcome\nassessment\nIncomplete\noutcome data\nSelective\nreporting\nOther bias\n(ITT analysis)\nCarr et al. Low risk Low risk Low risk Low risk Low risk Low risk Low risk\nElaris (UF-1/2) Low risk Low risk Low risk Low risk Low risk Low risk Low risk\nArcher et al. Unclear risk of bias Unclear risk of bias Unclear risk of bias Unclear risk of bias Low risk Low risk Low risk\nNOTE: Weights are from random effects analysis\n.\n.\n.\nELA w/ ABT vs PBO\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 48.0%, p = 0.104)\nELA vs PBO\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 0.0%, p = 0.531)\nELA vs ELA w/ ABT\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 43.1%, p = 0.134)\nID\nStudy\n2.40 (0.89, 3.91)\n2.25 (1.45, 3.06)\n2.26 (1.51, 3.00)\n3.11 (2.37, 3.85)\n3.47 (2.70, 4.23)\n2.74 (2.21, 3.27)\n4.06 (1.80, 6.32)\n3.44 (2.38, 4.51)\n2.91 (2.03, 3.78)\n3.97 (3.11, 4.83)\n3.44 (2.61, 4.28)\n3.47 (3.03, 3.91)\n1.66 (−0.60, 3.92)\n1.19 (0.10, 2.28)\n0.65 (−0.28, 1.58)\n0.86 (0.26, 1.46)\n−0.02 (−0.61, 0.56)\n0.64 (0.12, 1.16)\nOR (95% CI)\n22/26\n51/65\n63/77\n141/206\n146/189\n423/563\n29/30\n60/65\n69/77\n87/104\n73/95\n318/371\n29/30\n60/65\n69/77\n87/104\n73/95\n318/371\nTreatment\nFirst\nEvents,\n5/15\n18/65\n25/78\n9/102\n9/94\n66/354\n5/15\n18/65\n25/78\n9/102\n9/94\n66/354\n22/26\n51/65\n63/77\n141/206\n146/189\n423/563\nTreatment\nSecond\nEvents,\n9.53\n21.59\n23.07\n23.21\n22.59\n100.00\n3.77\n17.13\n25.34\n26.15\n27.61\n100.00\n4.78\n15.65\n19.09\n30.01\n30.47\n100.00\nWeight\n%\n2.40 (0.89, 3.91)\n2.25 (1.45, 3.06)\n2.26 (1.51, 3.00)\n3.11 (2.37, 3.85)\n3.47 (2.70, 4.23)\n2.74 (2.21, 3.27)\n4.06 (1.80, 6.32)\n3.44 (2.38, 4.51)\n2.91 (2.03, 3.78)\n3.97 (3.11, 4.83)\n3.44 (2.61, 4.28)\n3.47 (3.03, 3.91)\n1.66 (−0.60, 3.92)\n1.19 (0.10, 2.28)\n0.65 (−0.28, 1.58)\n0.86 (0.26, 1.46)\n−0.02 (−0.61, 0.56)\n0.64 (0.12, 1.16)\nOR (95% CI)\n22/26\n51/65\n63/77\n141/206\n146/189\n423/563\n29/30\n60/65\n69/77\n87/104\n73/95\n318/371\n29/30\n60/65\n69/77\n87/104\n73/95\n318/371\nTreatment\nFirst\nEvents,\n0−6.32 0 6.32\nFavours First InterventionFavours Second Intervention\nFig. 2 Forest plot comparing the primary outcome (women with MBV ≤ 80 ml/cycle and ≥ 50% reduction from baseline) across treatments\nAli et al. Middle East Fertility Society Journal           (2021) 26:20 Page 7 of 12\n\nNOTE: Weights are from random effects analysis\n.\n.\n.\nELA w/ ABT vs PBO\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 0.0%, p = 0.963)\nELA vs PBO\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 0.0%, p = 0.960)\nELA vs ELA w/ ABT\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 0.0%, p = 0.877)\nID\nStudy\n2.78 (−0.15, 5.70)\n3.83 (1.78, 5.87)\n2.97 (1.48, 4.46)\n3.00 (1.96, 4.05)\n3.12 (2.08, 4.17)\n3.10 (2.49, 3.72)\n4.74 (1.79, 7.68)\n5.22 (3.15, 7.28)\n4.31 (2.82, 5.81)\n4.45 (3.33, 5.57)\n4.76 (3.58, 5.93)\n4.61 (3.96, 5.27)\n2.05 (0.82, 3.29)\n1.39 (0.60, 2.18)\n1.34 (0.62, 2.06)\n1.45 (0.87, 2.03)\n1.63 (0.95, 2.32)\n1.50 (1.17, 1.83)\nOR (95% CI)\n8/26\n26/60\n23/66\n88/183\n91/172\n236/507\n22/28\n43/57\n45/67\n75/94\n69/81\n254/327\n22/28\n43/57\n45/67\n75/94\n69/81\n254/327\nTreatment\nFirst\nEvents,\n0/17\n1/61\n2/75\n4/91\n4/85\n11/329\n0/16\n1/61\n2/75\n4/91\n4/85\n11/328\n8/25\n26/60\n23/66\n88/183\n91/172\n236/506\nTreatment\nSecond\nEvents,\n4.43\n9.11\n17.02\n34.86\n34.58\n100.00\n4.98\n10.12\n19.34\n34.34\n31.22\n100.00\n7.06\n17.21\n20.81\n31.84\n23.08\n100.00\nWeight\n%\n2.78 (−0.15, 5.70)\n3.83 (1.78, 5.87)\n2.97 (1.48, 4.46)\n3.00 (1.96, 4.05)\n3.12 (2.08, 4.17)\n3.10 (2.49, 3.72)\n4.74 (1.79, 7.68)\n5.22 (3.15, 7.28)\n4.31 (2.82, 5.81)\n4.45 (3.33, 5.57)\n4.76 (3.58, 5.93)\n4.61 (3.96, 5.27)\n2.05 (0.82, 3.29)\n1.39 (0.60, 2.18)\n1.34 (0.62, 2.06)\n1.45 (0.87, 2.03)\n1.63 (0.95, 2.32)\n1.50 (1.17, 1.83)\nOR (95% CI)\n8/26\n26/60\n23/66\n88/183\n91/172\n236/507\n22/28\n43/57\n45/67\n75/94\n69/81\n254/327\n22/28\n43/57\n45/67\n75/94\n69/81\n254/327\nTreatment\nFirst\nEvents,\n0−7.68 0 7.68\nHigher in first treatmentHigher in second treatment\nNOTE: Weights are from random effects analysis\n.\n.\n.\nELA w/ ABT vs PBO\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 0.0%, p = 0.983)\nELA vs PBO\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 0.0%, p = 0.988)\nELA vs ELA w/ ABT\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 0.0%, p = 0.755)\nID\nStudy\n2.15 (−0.82, 5.11)\n3.17 (1.11, 5.22)\n3.08 (1.02, 5.14)\n3.00 (1.96, 4.05)\n3.12 (2.08, 4.17)\n3.03 (2.39, 3.68)\n4.08 (1.18, 6.99)\n4.34 (2.30, 6.39)\n4.33 (2.30, 6.36)\n4.45 (3.33, 5.57)\n4.76 (3.58, 5.93)\n4.51 (3.82, 5.20)\n2.03 (0.81, 3.25)\n1.17 (0.41, 1.94)\n1.25 (0.50, 2.00)\n1.45 (0.87, 2.03)\n1.63 (0.95, 2.32)\n1.45 (1.12, 1.77)\nOR (95% CI)\n5/27\n17/60\n15/66\n88/183\n91/172\n216/508\n19/30\n32/57\n34/67\n75/94\n69/81\n229/329\n19/30\n32/57\n34/67\n75/94\n69/81\n229/329\nTreatment\nFirst\nEvents,\n0/17\n1/61\n1/75\n4/91\n4/85\n10/329\n0/17\n1/61\n1/75\n4/91\n4/85\n10/329\n5/27\n17/60\n15/66\n88/183\n91/172\n216/508\nTreatment\nSecond\nEvents,\n4.72\n9.80\n9.79\n38.00\n37.69\n100.00\n5.60\n11.30\n11.45\n37.53\n34.12\n100.00\n7.23\n18.33\n19.25\n31.99\n23.20\n100.00\nWeight\n%\n2.15 (−0.82, 5.11)\n3.17 (1.11, 5.22)\n3.08 (1.02, 5.14)\n3.00 (1.96, 4.05)\n3.12 (2.08, 4.17)\n3.03 (2.39, 3.68)\n4.08 (1.18, 6.99)\n4.34 (2.30, 6.39)\n4.33 (2.30, 6.36)\n4.45 (3.33, 5.57)\n4.76 (3.58, 5.93)\n4.51 (3.82, 5.20)\n2.03 (0.81, 3.25)\n1.17 (0.41, 1.94)\n1.25 (0.50, 2.00)\n1.45 (0.87, 2.03)\n1.63 (0.95, 2.32)\n1.45 (1.12, 1.77)\nOR (95% CI)\n5/27\n17/60\n15/66\n88/183\n91/172\n216/508\n19/30\n32/57\n34/67\n75/94\n69/81\n229/329\n19/30\n32/57\n34/67\n75/94\n69/81\n229/329\nTreatment\nFirst\nEvents,\n0−6.99 0 6.99\nHigher in First TreatmentHigher in Second Treatment\nab\nFig. 3 Forest plots comparing: a suppression of bleeding and b amenorrhea, across treatments\nNOTE: Weights are from random effects analysis\n.\n.\n.\nELA w/ ABT vs PBO\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nSubtotal  (I−squared = 0.0%, p = 0.927)\nELA vs PBO\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nSubtotal  (I−squared = 66.0%, p = 0.053)\nELA vs ELA w/ ABT\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nSubtotal  (I−squared = 68.2%, p = 0.043)\nID\nStudy\n1.37 (0.44, 2.30)\n1.23 (0.49, 1.97)\n1.14 (0.45, 1.82)\n1.22 (0.78, 1.66)\n0.97 (0.13, 1.81)\n2.27 (1.44, 3.10)\n1.11 (0.42, 1.81)\n1.44 (0.66, 2.22)\n−0.40 (−1.29, 0.50)\n1.04 (0.23, 1.85)\n−0.02 (−0.68, 0.63)\n0.21 (−0.59, 1.01)\nOR (95% CI)\n21/34\n36/61\n39/74\n96/169\n25/48\n49/61\n37/71\n111/180\n25/48\n49/61\n37/71\n111/180\nTreatment\nFirst\nEvents,\n14/48\n19/64\n20/76\n53/188\n14/48\n19/64\n20/76\n53/188\n21/34\n36/61\n39/74\n96/169\nTreatment\nSecond\nEvents,\n22.59\n35.70\n41.71\n100.00\n31.75\n32.12\n36.13\n100.00\n30.42\n32.59\n36.99\n100.00\nWeight\n%\n1.37 (0.44, 2.30)\n1.23 (0.49, 1.97)\n1.14 (0.45, 1.82)\n1.22 (0.78, 1.66)\n0.97 (0.13, 1.81)\n2.27 (1.44, 3.10)\n1.11 (0.42, 1.81)\n1.44 (0.66, 2.22)\n−0.40 (−1.29, 0.50)\n1.04 (0.23, 1.85)\n−0.02 (−0.68, 0.63)\n0.21 (−0.59, 1.01)\nOR (95% CI)\n21/34\n36/61\n39/74\n96/169\n25/48\n49/61\n37/71\n111/180\n25/48\n49/61\n37/71\n111/180\nTreatment\nFirst\nEvents,\n0−3.1 0 3.1\nFavours First TreatmentFavours Second Treatment\nFig. 4 Forest plot comparing across interventions the number of women with ≥ 1 g/dL increase in hemoglobin levels after treatment\nAli et al. Middle East Fertility Society Journal           (2021) 26:20 Page 8 of 12\n\nthis analysis while substantial could be explained by\nthe differences in the follow-up periods of the 2 trials.\nThese findings are consistent with the results of the\nphase 3 trials which similarly reported that elagolix\n(with or without add-back) significantly improved\nhemoglobin values. Moreover, the lack of add-back\ntherapy’s role in improving hemoglobin levels is fur-\nther corroborated by the overlapping confidence in-\ntervals reported by UF-1 and UF-2 for both\ninterventions (elagolix with and without add-back\ntherapy) compared to placebo, concerning the per-\ncentage difference of women who observed a ≥ 2g / d L\nincrease in hemoglobin levels. While the improvement\nin hemoglobin levels in the elagolix groups compared\nto placebo may be attributed to the corresponding de-\ncrease in MBL (primary outcome), we found no evi-\ndence explaining the lack of difference between the\nelagolix groups (with a nd without add-back).\nWhen pooling safety related endpoints, patients\ngiven elagolix had a significantly higher overall inci-\ndence of adverse events when compared to the pla-\ncebo group. However, the incidence of serious life-\nthreatening adverse events was not shown to vary be-\ntween groups, attesting to the safety of the drug.\nWith the exception of hot flashes, headaches and\nnausea, most adverse events did not vary significantly\nbetween the intervention and placebo group and\ntherefore could not be directly attributed to the drug\nitself. Furthermore, analysis revealed that headaches\nand hot flashes were more frequently observed in the\nelagolix only group, which may be attributed to the\nestrogen diminishing impact of elagolix [ 25, 26]. The\nhigh incidence of nausea observed in the add-back\ngroup may be due to the side effects of the estradiol\nadministered as part of the add-back treatment\nregimen.\nNOTE: Weights are from random effects analysis\n.\n.\n.\nELA w/ ABT vs PBO\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 53.1%, p = 0.074)\nELA vs PBO\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 30.7%, p = 0.217)\nELA vs ELA w/ ABT\nArcher et al\nCarr ELA 300 mg BD\nCarr ELA 600 mg QD\nELARIS UF−1\nELARIS UF−2\nSubtotal  (I−squared = 0.0%, p = 0.801)\nID\nStudy\n0.23 (−1.63, 2.08)\n−1.87 (−4.02, 0.27)\n1.44 (−0.77, 3.65)\n−1.25 (−2.70, 0.20)\n1.27 (−0.84, 3.38)\n−0.12 (−1.38, 1.14)\n−0.62 (−2.93, 1.69)\n−0.74 (−2.17, 0.69)\n1.68 (−0.49, 3.85)\n−0.55 (−2.01, 0.91)\n1.41 (−0.80, 3.62)\n0.04 (−0.95, 1.03)\n−0.84 (−3.30, 1.62)\n1.13 (−1.16, 3.42)\n0.24 (−1.12, 1.59)\n0.70 (−0.92, 2.32)\n0.13 (−1.12, 1.39)\n0.29 (−0.43, 1.01)\nOR (95% CI)\n2/27\n1/65\n4/77\n3/206\n7/189\n17/564\n1/30\n3/65\n5/77\n3/104\n4/95\n16/371\n1/30\n3/65\n5/77\n3/104\n4/95\n16/371\nTreatment\nFirst\nEvents,\n3/50\n6/65\n1/78\n5/102\n1/94\n16/389\n3/50\n6/65\n1/78\n5/102\n1/94\n16/389\n2/27\n1/65\n4/77\n3/206\n7/189\n17/564\nTreatment\nSecond\nEvents,\n20.84\n18.05\n17.46\n25.27\n18.38\n100.00\n14.31\n27.61\n15.75\n27.01\n15.32\n100.00\n8.62\n9.94\n28.40\n19.90\n33.14\n100.00\nWeight\n%\n0.23 (−1.63, 2.08)\n−1.87 (−4.02, 0.27)\n1.44 (−0.77, 3.65)\n−1.25 (−2.70, 0.20)\n1.27 (−0.84, 3.38)\n−0.12 (−1.38, 1.14)\n−0.62 (−2.93, 1.69)\n−0.74 (−2.17, 0.69)\n1.68 (−0.49, 3.85)\n−0.55 (−2.01, 0.91)\n1.41 (−0.80, 3.62)\n0.04 (−0.95, 1.03)\n−0.84 (−3.30, 1.62)\n1.13 (−1.16, 3.42)\n0.24 (−1.12, 1.59)\n0.70 (−0.92, 2.32)\n0.13 (−1.12, 1.39)\n0.29 (−0.43, 1.01)\nOR (95% CI)\n2/27\n1/65\n4/77\n3/206\n7/189\n17/564\n1/30\n3/65\n5/77\n3/104\n4/95\n16/371\n1/30\n3/65\n5/77\n3/104\n4/95\n16/371\nTreatment\nFirst\nEvents,\n0−4.02 0 4.02\nHigher in First TreatmentHigher in Second Treatment\nFig. 5 Forest plot comparing across interventions the incidence of serious adverse events\nAli et al. Middle East Fertility Society Journal           (2021) 26:20 Page 9 of 12\n\nCarr et al. and Schlaff et al. also reported decrease\nin bone mineral density (BMD) as a secondary side\neffect of the use of elagolix. All 3 trials reported a\nsignificantly decreased BMD in the elagolix only\ngroup compared to the placebo group. This is inline\nwith previous studies correlating low serum estrogen\nlevels to loss of BMD [ 27]. Add-back therapy was\nshown to be effective in curtailing this loss in bone\ndensity, with Schalff et al. reporting no significant dif-\nference in BMD between placebo and add-back\ngroups, and Carr reporting the same with one excep-\ntion (total hip density in the 300 mg BD elagolix\narm).\nA few limitations should be kept in mind when\nanalyzing the results of this meta-analysis. Firstly be-\ncause of the novelty of the drug, this analysis only\nincluded 4 trials, and more would be required to\nform a conclusive result. Secondly, any dose-\ndependent effect of add-back therapy must be inves-\ntigated to find the perfect balance between the safety\nand therapeutic of this treatment. Further trials in-\nvestigating the safety and efficacy of different add-\nback therapies at different doses with elagolix should\nbe conducted in order to reveal a potentially better\ntreatment solution.\nConclusion\nIn conclusion, pooling of results from 4 high-quality\ntrials provides strong evidence for the use of elagolix\nas a treatment option for heavy menstrual bleeding\nin patients with uterine leiomyomas. Analysis\nshowed marked improvement in all efficacy end-\npoints taken into consideration in this review. Add-\nitionally, trials have demonstrated that the drug is\nrelatively safe, with generally mild to moderate ad-\nverse effects and no serious ( life-threatening) side-\nFig. 6 Forest plot comparing across interventions the overall incidence of adverse events\nAli et al. Middle East Fertility Society Journal           (2021) 26:20 Page 10 of 12\n\neffects. Moreover, these results advocate for the use\nof add-back therapy (combin ed estradiol and proges-\nterone) with elagolix, as its inclusion in the treat-\nment regimen resulted in a significant attenuation of\nelagolix-associated hypoestrogenic effects, leading to\na much safer therapeutic course.\nAbbreviations\nHMB: Heavy menstrual bleeding; MBL: Menstrual blood loss; PBO: Placebo;\nLOR: Log-odds ratio; CI: Confidence interval; SPRMs: Selective progesterone\nreceptor modulators; GnRH: Gonadotropin-releasing hormone;\nRCT: Randomized control trial; CRoB Tool: Cochrane Risk of Bias Tool;\nBMD: Bone mineral density; E: Elagolix; EA: Elagolix with add-back\nSupplementary Information\nThe online version contains supplementary material available at https://doi.\norg/10.1186/s43043-021-00064-5.\nAdditional file 1: Figure S1. Common adverse events in Elagolix only\ngroup (ELA) vs placebo group (PBO). Figure S2. Common adverse\nevents in Elagolix with add-back group (ELA w/ ABT) vs placebo group\n(PBO). Figure S3. Common adverse events in Elagolix only (ELA) vs Ela-\ngolix with Add-back therapy (ELA w/ ABT). Figure S4. Funnel plots for\nthe pooling of the primary outcome: (a) Elagolix vs Placebo; (b) Elagolix\nwith add back vs Placebo; (c) Elagolix vs Elagolix with add back. Figure\nS5. Leave one out sensitivity analysis for the primary outcome (Elagolix\nonly vs Placebo). Figure S6. Leave one out sensitivity analysis (Elagolix\nwith add-back vs Placebo). Figure S7. Leave one out sensitivity analysis\n(Elagolix only vs Elagolix with add-back).\nAcknowledgements\nNot Applicable\nAuthors’ contributions\nIn addition to having read and approved the final manuscript, the following\nare the contributions of each specific author: MA: conceptualization and\ndesign of the study, search and screening of studies, data analysis and\ninterpretation, drafting of the manuscript. AKH: design of the study, final\nreview and editing of the manuscript. HJ: conceptualization and design of\nthe study, data analysis and interpretation, drafting of the manuscript. FZ:\nsearch and screening of studies, data extraction, drafting of the manuscript.\nZS: data extraction, review and drafting of the manuscript. The author(s) read\nand approved the final manuscript.\nFunding\nNot applicable.\nAvailability of data and materials\nNot applicable.\nDeclarations\nEthics approval and consent to participate\nNot applicable.\nConsent for publication\nNot applicable.\nCompeting interests\nNot applicable.\nAuthor details\n1Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.\n2Obstetrics & Gynaecology Unit I, Dow University of Health Sciences, Karachi,\nPakistan.\nReceived: 23 March 2021 Accepted: 11 June 2021\nReferences\n1. 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