BACKGROUND: Elagolix, an approved non-peptide GnRH antagonist, shows promise in relieving endometriosis-related pain, but its short- and mid-term efficacy and potential side effects are still under investigation.
OBJECTIVE: The aim is to provide data for therapeutic applications by methodically evaluating elagolix\'s safety and effectiveness in treating endometriosis-related pain.
METHODS: Databases such as PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and others were thoroughly searched. The search time was from the establishment date to September 2023. The study included randomized controlled trials (RCTs) that compared the efficacy of elagolix versus placebo in treating endometriosis-associated pain. After data extraction and literature scanning, quality assessment was carried out using Quality evaluation was carried out using the bias risk assessment tool suggested by the Cochrane Reviewers\' Handbook 5.1.0 after literature screening and data extraction. Stata 15.0 was used to do the meta-analysis.
RESULTS: In total, five RCTs involving 2056 patients were included in the analysis. The meta-analysis demonstrated a significant superiority of elagolix over placebo in the management of endometriosis-related pain, specifically in endometriosis pain [WMD=-0.77, 95% CI (-1.00, -0.53), P<0.001], as well as in non-menstrual pelvic pain, daily assessment of dysmenorrhea (DYS), and dyspareunia (DYSP), all of which are associated with endometriosis. Regarding safety, no discernible variation was observed in the incidence of serious adverse responses between the elagolix and placebo groups [RR=0.90, 95% CI (0.58, 1.40), P=0.643]. Conversely, the elagolix group exhibited a significantly higher incidence rate of general adverse responses [RR = 1.34, 95% CI (1.18, 1.52), P<0.001] compared to the control group.
CONCLUSIONS: The efficacy of elagolix in reducing pain in premenopausal women with endometriosis has been demonstrated over the short- to mid-term. However, careful monitoring for potential adverse effects is essential throughout the treatment duration.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects.
OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol/0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain.
METHODS: This ongoing, 48-month, phase 3 study consists of a 12-month double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The coprimary endpoints were proportion of patients with clinical improvement (termed \"responders\") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy vs placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density.
RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% vs 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% vs 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12.
CONCLUSIONS: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was <1% and was attenuated compared with bone loss observed with elagolix monotherapy.

OBJECTIVE: To characterise contemporary trends in the hormonal management of endometriosis in adolescent and young adult patients with biopsy-proven endometriosis.
METHODS: Retrospective chart review of women aged 14-25 years who underwent laparoscopy for pelvic pain with biopsy-proven endometriosis between January 2011 and September 2020 at an academic tertiary hospital system. The final sample included 91 patients with biopsy-confirmed endometriosis.
RESULTS: Combined oral contraceptives (COCs) were the most common initial treatment (64% of patients). Progestin-only formulations (low- and high-dose norethindrone acetate) were offered to younger patients (age 15.9 ± 2.7 years) than those offered COCs (19.9 ± 3.3 years) and levonorgestrel intrauterine devices (LNG-IUDs) (21.9 ± 1.7 years). Current treatments varied widely and included COCs (32%), LNG-IUDs (18%), oral progestins (low- and high-dose norethindrone, medroxyprogesterone) (14%), elagolix (9%), and leuprolide (8%). Oral adjuncts to LNG-IUD were common: usually low- or high-dose norethindrone (37% of patients with an LNG-IUD), but also included progesterone, COCs, and elagolix.
CONCLUSIONS: Oral progestins, LNG-IUDs, and COCs were the mainstay of initial treatment. Subsequent treatments varied widely and included COCs, LNG-IUDs, oral progestins, elagolix, leuprolide, and combinations of these agents. We observed that most young women switched between therapies, suggesting that a personalised approach is often used to determine treatment plans among the wide range of options currently available. This study helps define the spectrum of treatment regimens for endometriosis in adolescent females.

UNASSIGNED: Elagolix is approved for the treatment of moderate-to-severe pain associated with endometriosis. However, the long-term safety of elagolix in a large sample of real-world patients is unknown.
UNASSIGNED: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) reports were collected and analyzed from January 2019 to June 2023. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed in data mining to quantify the signals of elagolix-related adverse events (AEs).
UNASSIGNED: After removing the non-drug-related AE signals, we detected several AE signals such as hot flushes, bone pain, suicidal ideation, depression, and increased liver enzymes, which were known during the clinical trial phase. In addition to this, we detected several unexpected important AEs that were not mentioned in the drug insert, including cystitis interstitial, parosmia, and epiploic appendagitis. The median onset time of elagolix-associated AEs was 28.5 days.
UNASSIGNED: Our study provides a comprehensive picture of the safety of elagolix in the post-marketing setting, while also identifying potential new AE signals. These findings emphasize the importance of continued monitoring of the potential risks of elagolix.

UNASSIGNED: Uterine fibroids, the most prevalent benign tumors among reproductive-age women, pose treatment challenges that range from surgical interventions to medical therapies for symptom control. Progestins and estroprogestins effectively manage uterine bleeding by suppressing dysfunctional endometrium over fibroids. While GnRH agonists represent a crucial milestone in symptom treatment, their prolonged use results in menopausal-like symptoms and irreversible bone mineral density loss. Advancements in understanding fibroid pathophysiology have prompted the exploration of new compounds to overcome current therapy limitations.
UNASSIGNED: This manuscript offers an updated overview of investigational drugs for symptomatic uterine fibroids.
UNASSIGNED: Despite ulipristal acetate\'s well-established efficacy as a selective progesterone receptor modulator (SPRM) in fibroid treatment, its prescription has declined due to the rare but severe risk of liver damage. Oral GnRH antagonists, like elagolix, relugolix, and linzagolix, with their novel pharmacodynamic properties, are gaining traction in fibroid management, inducing a dose-dependent reduction in circulating sex hormone levels. Ongoing research on natural compounds, such as vitamin D and epigallocatechin gallate (EGCG), presents emerging options for treating uterine fibroids. This evolving landscape reflects the ongoing efforts to improve therapeutic outcomes for individuals with symptomatic uterine fibroids.

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5 mg as the morning dose and an elagolix 300 mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300 mg/1 mg/0.5 mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.

BACKGROUND: The injectable GnRH antagonists have traditionally been used for ovulation suppression during controlled ovarian hyperstimulation in IVF, leading to increased painful daily injections and cost. The use of the oral GnRH antagonist elagolix for ovulation suppression in IVF has not been studied.
METHODS: A retrospective cohort study of patients undergoing IVF received either oral elagolix 50 mg every other day or ganirelix/cetrotide injection daily for ovulation suppression during controlled ovarian hyperstimulation. A total of 269 patients, 173 in the elagolix group and 96 in the ganirelix/cetrotide group, were included. The main outcome was the suppression of luteinizing hormone (LH) blood levels reflecting ovulation suppression.
RESULTS: The age, body mass index, AMH levels, baseline FSH, antral follicles count, the dose of medications used, the number of days of ovarian stimulation, and peak estradiol (E2) levels were similar in both groups. When blood LH and E2 levels were measured before the intake and the day after intake of either elagolix or ganirelix/cetrotide, both groups had significant and similar drop in LH levels and increase in E2 levels. When comparing the IVF cycle outcomes in both groups, the number of oocytes retrieved, the number of mature oocytes, the fertilization rate, the blastocyst formation rate, the euploidy rate and the endometrial lining thickness at the time of the trigger were all similar.
CONCLUSIONS: Oral GnRH antagonist, a much cheaper and less invasive medication that is used at a lower frequency, showed comparable ovulation suppression to the costly injectable GnRH antagonist. Further studies are required to evaluate the effect of oral GnRH antagonist on endometrial lining receptivity and pregnancy outcomes especially when using fresh embryo transfer IVF protocols.

Current medical treatment options for endometriosis associated pains are inadequate. Evidence on effects of nonsteroidal anti-inflammatory drugs is scarce. Around one third of patients are not responsive to oral contraceptives or progestins due to progesterone resistance. Gonadotropin-releasing hormone (GnRH) agonists can only be used for a short duration because of associated side effects. Oral GnRH antagonists, including elagolix, relugolix, and linzagolix allow oral administration, induce dose dependent reduction of estradiol levels, do not cause initial flare up of endometriosis symptoms, and allow the fast return of ovarian function and menstruation after discontinuation. Elagolix at a low dose of 150 mg once daily, or the higher dose of 200 mg twice daily, significantly increased the proportion of women achieving clinically meaningful decline of dysmenorrhea, noncyclic pelvic pain, and dyspareunia. Relugolix at an oral dose of 40 mg/day results in improvement in different forms of endometriosis related pelvic pain, with an efficacy and side effect profile similar to that of GnRH agonists. Adding 1 mg of estradiol and 0.5 mg of norethindrone to 40 mg of relugolix (relugolix combination therapy) allows extension of treatment to 24 weeks with maintained efficacy and an improved side effect profile. Linzagolix, in a dose of 75 mg/day, can be used alone to treat endometriosis associated pain. For severe pelvic pain and dyspareunia, linzagolix can be used in a high dose of 200 mg/day with hormonal add-back therapy to preserve bone health.

Novel gonadotrophin releasing hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix and linzagolix have assessed treatment efficacy for fibroid-related heavy menstrual blood loss in comparison to placebo. Marketing authorization has been granted by several agencies including those in Europe, the United Kingdom and the United States. While the registration trials report a robust effect on the reduction of heavy menstrual blood loss and improvement in quality of life scores, reticence is advised before widespread prescription. In this review, we demonstrate limitations in the trial data, namely a lack of generalizability due to the restricted study population, the lack of transparency in the distribution of disease-level characteristics limiting the predictability of treatment success in the real-world diverse population, and the absence of any comparison to current alternative treatment methods. Importantly, no clinically meaningful volume reductions were found with GnRH antagonist combination preparations, and long-term safety data, particularly concerning modest but stable bone mineral density decline, need further addressing. Symptoms related to uterine fibroids adversely affect many women\'s quality of life and effective medical treatments are lacking. However, despite the urgent need for conservative treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness and cost-effectiveness in a representative population and are compared with alternative treatment methods before introduction into mainstream clinical practice.

UNASSIGNED: Evaluate the efficacy and safety of elagolix, a GnRH antagonist, to treat polycystic ovarian syndrome (PCOS).
UNASSIGNED: A phase 2, multicenter, double-blind, randomized, placebo-controlled trial.
UNASSIGNED: Outpatient and academic medical centers.
UNASSIGNED: One hundred fourteen women with PCOS (aged 18-35 years, body mass index 18.5-38 kg/m2).
UNASSIGNED: Patients were randomized 2:2:2:2:2:3 to elagolix (25 mg twice daily, 50 mg once daily, 75 mg twice daily, 150 mg once daily, and 300 mg twice daily) or placebo.
UNASSIGNED: The primary endpoint was menstrual cycle normalization (defined as 2 menstrual cycles 21-35 days in length during the 4-month treatment period). The secondary endpoint was change from baseline to week 1 in the area under the luteinizing hormone (LH) serum concentration-time curve (AUC). Additional endpoints included change from baseline in serum hormone levels.
UNASSIGNED: No significant improvement in restoring normal menstrual cycles was observed in treated subjects; 3 of 114 patients met the primary endpoint. Six patients experienced progesterone elevations indicative of ovulation. The LH levels decreased from baseline to week 16, and LH AUC was significantly reduced from baseline to week 1 in all elagolix treatment groups (P<.1 vs placebo). Follicle-stimulating hormone (FSH) levels generally remained stable through week 16, with no significant differences in FSH AUCs. Serum estradiol and testosterone concentrations were consistently reduced from baseline in all elagolix dose groups compared with placebo. Adverse event rates were similar across treatment groups.
UNASSIGNED: Elagolix treatment did not normalize the ovulatory cycle in patients with PCOS.
UNASSIGNED: NCT03951077.