Norethisterone Research Articles

Thromboembolic safety of norethisterone vs levonorgestrel in combined oral contraceptive users: a pooled analysis of 4 large prospective cohort studies

BACKGROUNDNorethisterone (acetate) and levonorgestrel are marketed globally as components of combined oral contraceptives. Although guidelines recommend both as first-line combined oral contraceptives, no direct, comparative safety studies are available.OBJECTIVEWe directly compared the thromboembolic event risk associated with the use of norethisterone acetate-containing and levonorgestrel-containing combined oral contraceptives.STUDY DESIGNData regarding the cohorts of interest, norethisterone/norethisterone acetate (ethinylestradiol ≤30 µg) and levonorgestrel (ethinylestradiol ≤30 µg), were retrieved from a pooled dataset comprising 4 prospective, noninterventional, active-surveillance cohort studies in 14 European countries, the United States, and Canada, with similar study design but differing medication cohorts. Baseline characteristics and parameters of reproductive, contraceptive, and medical history were summarized using descriptive statistics. Propensity score subclassification was applied to balance baseline parameters between cohorts. Time-to-event analysis of venous thromboembolic events was performed on the basis of the extended Cox model to calculate crude and adjusted hazard ratios, including 95% confidence intervals. The time of venous thromboembolic events was censored at the end of the observation period for women who did not have an event. Women who dropped out or were lost to follow-up without reported venous thromboembolic events were censored at the time they last confirmed that they did not have an event.RESULTSThe pooled dataset included 235,437 combined oral contraceptive users who were followed up for a total of 571,163 women years. Among these, 40,142 women were users of norethisterone/norethisterone acetate (ethinylestradiol ≤30 µg), and 39,098 women were users of levonorgestrel (ethinylestradiol ≤30 µg), contributing 61,976 and 84,816 women years of observation, respectively. The observed prevalence of prognostic factors at baseline showed typical features of US and European combined oral contraceptive users. Both cohorts showed a similar, low rate of thromboembolic events, and we could exclude a 1.5-fold increased venous thromboembolism risk for norethisterone/norethisterone acetate relative to levonorgestrel (adjusted hazard ratio, 0.73; 95% confidence interval, 0.48–1.11).CONCLUSIONThese data confirm the similar risk profiles of norethisterone/norethisterone acetate and levonorgestrel regarding thromboembolic events in routine combined oral contraceptive use of around 80,000 women from Europe and the United States/Canada. The analysis provides reassurance for both combined oral contraceptive users and clinicians regarding the safety of oral contraceptives and potentially opens discussion on norethisterone acetate as a potential gold standard therapy in clinical and postmarket research alongside levonorgestrel-combined oral contraceptives.

Medroxyprogesterone acetate inhibits wound closure of human endometrial epithelial cells and stromal fibroblasts in vitro

Mucosal integrity in the endometrium is essential for immune protection. Since breaches or injury to the epithelial barrier exposes underlying tissue and is hypothesized to increase infection risk, we determined whether endogenous progesterone or three exogenous progestins (medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG)) used by women as contraceptives interfere with wound closure of endometrial epithelial cells and fibroblasts in vitro. Progesterone and LNG had no inhibitory effect on wound closure by either epithelial cells or fibroblasts. MPA significantly impaired wound closure in both cell types and delayed the reestablishment of transepithelial resistance by epithelial cells. In contrast to MPA, NET selectively decreased wound closure by stromal fibroblasts but not epithelial cells. Following epithelial injury, MPA but not LNG or NET, blocked the injury-induced upregulation of HBD2, a broad-spectrum antimicrobial implicated in wound healing, but had no effect on the secretion of RANTES, CCL20 and SDF-1α. This study demonstrates that, unlike progesterone and LNG, MPA and NET may interfere with wound closure following injury in the endometrium, potentially conferring a higher risk of pathogen transmission. Our findings highlight the importance of evaluating progestins for their impact on wound repair at mucosal surfaces.

The Effect of Time Since Surgical Diagnosis of Endometriosis on Treatment Outcomes with Relugolix Combination Therapy: Spirit Program

<h3>Study Objective</h3> To assess efficacy of relugolix combination therapy (Relugolix-CT) in women who were surgically diagnosed with endometriosis <5 years and ≥5 years ago. <h3>Design</h3> SPIRIT 1/2 were 24-week randomized, double-blind, placebo-controlled Phase 3 studies. <h3>Setting</h3> 124 (SPIRIT 1) and 95 (SPIRIT 2) clinical research centers globally. <h3>Patients or Participants</h3> Premenopausal women (age 18–50 years) with surgically diagnosed endometriosis, moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP). <h3>Interventions</h3> Once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) or placebo. <h3>Measurements and Main Results</h3> Change in dysmenorrhea/NMPP NRS scores and Endometriosis Health Profile-30 (EHP-30) pain domain scores analyzed in women with endometriosis diagnosis <5 years (N=579) and ≥5 years (N=255) ago. Baseline demographics/clinical characteristics were comparable between subgroups. Mean (standard deviation) time since surgical diagnosis for Relugolix-CT and for placebo: 2.1 (1.5) and 2.1 (1.5) years (<5-years subgroup); 8.0 (2.8) and 7.8 (2.3) years (≥5-years subgroup), respectively. With Relugolix-CT, mean dysmenorrhea NRS and EHP-30 pain domain score decreased significantly (both subgroups) vs placebo; mean NMPP NRS score decreased significantly in the <5-years subgroup (Table). <h3>Conclusion</h3> Relugolix-CT reduced dysmenorrhea and improved daily functioning in both groups: surgical diagnosis <5 years and ≥5 years ago. Reduction in NMPP was statistically significant in women with surgical diagnosis <5 years ago.

Recurrent Hemorrhagic Ascites in Endometriosis: A Case Series and Systematic Review

<h3>Study Objective</h3> To synthesize existing literature and contribute to the collective understanding of hemorrhagic ascites caused by endometriosis through a systematic review and description of three cases seen at our tertiary-care centre. <h3>Design</h3> The case series was conducted as a retrospective review of patients referred to our tertiary-care centre. The systematic review included all publications based on the keywords "endometriosis AND (plural effusion OR ascites) from CENTRAL (Cochrane Library, current issue), MEDLINE (Silver Platter) and EMBASE electronic databases between 1950-2021. <h3>Setting</h3> The three case series patients were seen at our tertiary-care centre. <h3>Patients or Participants</h3> All cases with endometriosis and ascites without any other identifiable cause were included in our systematic review. <h3>Interventions</h3> In Case 1, the patient underwent paracentesis and diagnostic laparoscopy followed by treatment with elagolix. In Case 2, the patient was treated conservatively with leuprolide acetate and norethindrone acetate. In Case 3, the patient underwent diagnostic laparoscopy followed by treatment with dienogest. <h3>Measurements and Main Results</h3> Data was collected from 130 cases (127 from the systematic review and 3 from our centre), including demographics, presenting symptoms, physical findings, management, and recurrence status. A strong correlation with nulliparity (78.2%) and black race (84.8%) was identified. Patients most commonly presented with bloating (62.1%) and abdominal distension on physical exam (54.4%). Ca-125 was frequently elevated (41.2%). A majority of patients received both medical (85.9%) and surgical management (85.7%). <h3>Conclusion</h3> This systematic review is the largest and most comprehensive review of hemorrhagic ascites in endometriosis. This rare form of endometriosis presents similarly to ascites of other etiologies, leading to diagnostic uncertainty, and may disproportionately affect black women. Although many patients undergo surgery as part of diagnosis, medical management may sufficiently treat this condition.

Non-Contraceptive Progestins and Risk of Venous Thromboembolism: A Nested Case-Control Study of the Marketscan Databases

<h3>Study Objective</h3> To evaluate for a dose-response relationship in the association between progestins used for non-contraceptive indications (e.g., endometriosis) and venous thromboembolism (VTE). <h3>Design</h3> Nested case-control study. <h3>Setting</h3> The IBM® MarketScan® Databases include routinely collected inpatient, outpatient, and pharmacy claims data among privately insured individuals in the US. <h3>Patients or Participants</h3> Records of 45 million women aged 15-49 years old were evaluated from 2009-2018. Cases with VTE (n=21,405) were identified by validated ICD-9/10 codes and excluded for recent pregnancy, recent estrogen prescription, or indications for ultra-high dose progestins (e.g., endometrial intraepithelial neoplasia). Controls (n=107,025) were individually age-matched 5:1 by risk set sampling. <h3>Interventions</h3> N/A. <h3>Measurements and Main Results</h3> Oral progestin exposures and covariates were defined by prescription claims and ICD-9/10 codes, respectively, within 1 year before the index date. Multivariate conditional logistic regression models determined odds ratios with 95% confidence intervals adjusted for VTE risk factors. The dose-response relationship was assessed by two separate exploratory analyses. The first analysis compared new and chronic use with non-use. The second analysis evaluated progestin exposure as a weighted average daily dose. Significance was set at p<0.01 to allow for multiple comparisons. Odds of VTE were significantly increased for current use of norethindrone acetate (new users aOR 4.97 [2.96-8.35], n=83; chronic users aOR 2.28 [1.48-3.51], n=118) and current use of medroxyprogesterone acetate (new users aOR 2.08 [1.47-2.96], n=194; chronic users aOR 1.76 [1.18-2.63], n=145), compared with non-use. Comparisons between new and chronic use were not significant. Odds of VTE were directly proportional to progestin dose: +22% (aOR 1.22 [1.09-1.36]) for each 2.5 mg/day increase in norethindrone acetate and +19% (aOR 1.19 [1.08-1.30]) for each 5 mg/day increase in medroxyprogesterone acetate. <h3>Conclusion</h3> Non-contraceptive progestins are associated with increased VTE risk. This study provides the first assessment and support of the dose-response relationship. Clinicians should consider using the lowest effective dose to balance risks and benefits.

Sustained Efficacy and Safety of Relugolix Combination Therapy in Women with Endometriosis-Associated Pain: Spirit 52-Week Data

<h3>Study Objective</h3> To evaluate long-term safety and efficacy of relugolix combination therapy (Relugolix-CT) to treat endometriosis-associated pain. <h3>Design</h3> SPIRIT Extension was a Phase 3, open-label, single-arm, 80-week study. <h3>Setting</h3> 170 clinical research centers globally. <h3>Patients or Participants</h3> Premenopausal women (age 18–50 years) with endometriosis, moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP) at baseline who completed the 24-week pivotal studies (SPIRIT 1/2) and were eligible to participate were enrolled. <h3>Interventions</h3> Once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg). <h3>Measurements and Main Results</h3> Co-primary endpoints: proportion of dysmenorrhea/NMPP responders at Week 52, using Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable). Dysmenorrhea/NMPP responder: women who achieved a clinically meaningful reduction from baseline in NRS score (2.8/2.1, respectively) without increased analgesic use. Secondary endpoints: change in Endometriosis Health Profile-30 (EHP-30) pain domain scores, analgesic/opioid use. Safety endpoints: adverse events, bone mineral density (BMD) evaluation. Of 1,261 women randomized in SPIRIT 1/2, 802 enrolled in the extension; 681 completed 52 weeks of treatment. Data are reported for women who received Relugolix-CT through 52 weeks. The proportion of responders for dysmenorrhea was 84.8% and 73.3% for NMPP. NRS least squares (LS) mean scores for dysmenorrhea, NMPP and dyspareunia decreased from 7.4 (severe), 6.0 (moderate) and 5.9 (moderate) at pivotal baseline to 1.3 (mild), 2.2 (mild) and 2.4 (mild) at Week 52, equating to 82.8%, 62.9% and 60.1% reductions. Daily functioning (EHP-30 pain domain score) improved (–38.1 point); most women (85.6%) were opioid-free at Week 52. No disproportionate increase in adverse event incidence and no new safety signals were identified. Lumbar spine BMD was preserved, with LS mean change from baseline to Week 52 of –0.81% (95% CI: –1.26, –0.36). <h3>Conclusion</h3> Relugolix-CT was well tolerated and demonstrated sustained improvement of endometriosis-associated pain and maintenance of BMD through 52 weeks.

The Role of Progestogens in Menopausal Hormone Therapy.

Progestogens are steroid compounds that have the ability to induce secretory transformation in the endometrium and are utilized in menopausal hormone therapy to prevent endometrial hyperplasia and endometrial cancer. Progestogens can be derived from 21-carbon or 19-carbon steroid cytoskeletons and thus have different properties and metabolic effects beyond the progestational effects on the endometrium. This limited review will focus on the available progestogens utilized in combination hormone therapy including progesterone, medroxyprogesterone acetate, norethindrone, norethindrone acetate, levonorgestrel, and drospirenone. The impact of progestogens on a variety of target tissues including the endometrium, breast, cardiovascular system, brain, and bone, will be reviewed. Last, the current clinical regimens that can be utilized by clinicians will be discussed.

Norethisterone exposure alters the transcriptome of Marine Medaka (Oryzias melastigma) larvae

ABSTRACT Norethisterone (NET) is one of the earliest synthetic progestins. Its widespread and long-term use means that NET is often detected on the surface and in groundwater samples, which may cause harm to aquatic organisms. Marine medaka (Oryzias melastigma) is a brackish fish, often used in ecotoxicology studies. In this study, the effect of norethisterone exposure on the transcriptome of marine medaka larvae was analyzed. Larvae were exposed to 10 ng/L NET for 24 h, then RNA-Seq was performed. Exposure to 10 ng/L NET resulted in 306 up-regulated and 516 down-regulated genes. An enrichment analysis revealed that differentially expressed genes (DEGs) were significantly enriched in metabolic and biosynthetic pathways, including DNA replication, proteasome, steroid biosynthesis, and other amino acid metabolism pathways. In the DNA replication pathway, all the DEGs were down-regulated, while in the steroid biosynthesis pathway, sqle, hmgcr, dhcr7, and dhcr24 were down-regulated. Quantitative real-time PCR (qPCR) was used to verify 12 DEGs, confirming that the validity of the RNA-Seq analysis. These results show that even low environmental concentrations of NET can lead to transcription level changes of genes related to fish growth and development, which may have adverse effects on the early development and growth of aquatic organisms. Highlights Transcriptomes from norethisterone-exposed marine medaka larvae were obtained A total of 822 differentially expressed genes were identified Norethisterone affected 155 pathways, including DNA replication.

ASSESSMENT OF COMMON ADVERSE EVENTS OF RELUGOLIX COMBINATION THERAPY IN PREMENOPAUSAL WOMEN TREATED FOR SYMPTOMATIC ESTROGEN-DRIVEN CONDITIONS: LIBERTY AND SPIRIT STUDIES

Relugolix is a once-daily, oral nonpeptide gonadotropin-releasing hormone receptor antagonist being developed in combination with estradiol (E2) and norethindrone acetate (NETA) to treat heavy menstrual bleeding (HMB) associated with uterine fibroids (UF) and moderate-to-severe pain associated with endometriosis (EM). In the Phase 3 LIBERTY 1/2 trials for UF (n=770), relugolix combination therapy (Rel-CT [once-daily relugolix 40 mg, E2 1 mg, NETA 0.5 mg]) reduced HMB vs placebo. In the SPIRIT 1/2 trials for EM (n=1251), Rel-CT reduced dysmenorrhea, non-menstrual pelvic pain and dyspareunia vs placebo.

RELUGOLIX COMBINATION THERAPY IMPROVES MULTIPLE DIMENSIONS OF QUALITY OF LIFE IN WOMEN WITH ENDOMETRIOSIS-ASSOCIATED PAIN: RESULTS FROM THE SPIRIT PROGRAM

Endometriosis has a significant impact on women’s physical, social, and emotional life. In the SPIRIT trials, relugolix combination therapy (Rel-CT: relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) significantly reduced dysmenorrhea, non-menstrual pelvic pain (NMPP) and dyspareunia vs placebo in premenopausal women with endometriosis-associated pain. Here, the effect of Rel-CT on health-related quality of life (QoL) domains, assessed using the Endometriosis Health Profile (EHP)-30 questionnaire, are reported.

LIBERTY RANDOMIZED WITHDRAWAL STUDY: 2-YEAR EFFICACY AND SAFETY OF RELUGOLIX COMBINATION THERAPY IN WOMEN WITH HEAVY MENSTRUAL BLEEDING ASSOCIATED WITH UTERINE FIBROIDS

In the pivotal LIBERTY 1 and 2 trials and Long-Term Extension (LTE) study, once-daily relugolix combination therapy (Rel-CT: relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) reduced menstrual blood loss (MBL) volume and pain in women with uterine fibroids (UF). Rel-CT was well tolerated, with preservation of bone mineral density (BMD) through 52 weeks. Here we report results of the Phase 3 LIBERTY randomized withdrawal study (RWS), designed to evaluate the efficacy and safety of Rel-CT for up to 2 years.

EFFECTS OF RELUGOLIX COMBINATION THERAPY ON BONE MINERAL DENSITY THROUGH 2 YEARS IN WOMEN WITH HEAVY MENSTRUAL BLEEDING ASSOCIATED WITH UTERINE FIBROIDS

Relugolix 40 mg is a non-peptide gonadotropin-releasing hormone receptor antagonist being developed for use in combination with estradiol 1 mg and norethindrone acetate 0.5 mg (relugolix combination therapy; Rel-CT) to treat heavy menstrual bleeding (HMB) associated with uterine fibroids (UF). The rationale for combination therapy is to mitigate anticipated hypoestrogenic effects with relugolix monotherapy, including bone loss. Rel-CT preserved bone mineral density (BMD) in the pivotal LIBERTY 1/2 trials and Long-Term Extension (LTE) study.

INTEGRATED LONG-TERM BONE MINERAL DENSITY (BMD) OUTCOMES IN WOMEN RECEIVING RELUGOLIX COMBINATION THERAPY IN LIBERTY AND SPIRIT STUDIES VS NON-TREATED WOMEN

Relugolix combination therapy (Rel-CT [once-daily relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg]) is being developed to treat heavy menstrual bleeding associated with uterine fibroids (UF), and endometriosis-associated pain (EM). In the Phase 3 LIBERTY 1/2 trials and long-term extension (LTE) study for UF, Rel-CT maintained BMD through 52 weeks. In the SPIRIT 1/2 trials and LTE study for EM, Rel-CT minimized BMD loss through 24 weeks, after which BMD plateaued up to 52 weeks. Since the mean age of women in the UF studies was higher than that in the EM studies, a pooled population assessment was undertaken to determine if a single BMD profile with a full range of ages could be developed for Rel-CT.

O-131 The effect of time since surgical diagnosis of endometriosis on treatment outcomes with relugolix combination therapy in women with endometriosis-associated pain: SPIRIT program

Abstract Study question To assess the efficacy of Relugolix-CT vs placebo in women who were surgically diagnosed with endometriosis &amp;lt;5 and &amp;gt; = 5 years ago. Summary answer Treatment outcomes did not differ for dysmenorrhea and daily functioning between subgroups of patients with &amp;lt;5 years or ≥ 5 years since surgical diagnosis. What is known already Time since clinical manifestation and diagnosis of endometriosis may influence the treatment success of patients with endometriosis-associated pain. SPIRIT 1 and 2 were randomized, double-blind, placebo-controlled Phase 3 studies of Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) in premenopausal women (age 18–50 years) with surgically diagnosed endometriosis and a history of moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP). These studies previously demonstrated that Relugolix-CT significantly reduced dysmenorrhea and NMPP, and improved daily functioning measured by the Endometriosis Health Profile-30 (EHP-30) pain domain score vs placebo over 24 weeks. Study design, size, duration Premenopausal women with surgically diagnosed endometriosis and moderate-to-severe dysmenorrhea and NMPP at baseline were randomized 1:1:1 to 24 weeks of treatment with once daily oral Relugolix-CT, delayed Relugolix-CT (relugolix 40 mg monotherapy for 12 weeks followed by Relugolix-CT for 12 weeks), or placebo. The proportion of dysmenorrhea and NMPP responders at Week 24/End-of-Treatment (EoT), based on daily Numerical Rating Scale (NRS), and analgesic use status were co-primary endpoints. Participants/materials, setting, methods Pooled SPIRIT 1 and 2 data of patients who received 24 weeks of treatment with once daily Relugolix-CT (N = 418) or placebo (N = 416) are presented. Outcomes for the delayed Relugolix-CT group were only for the safety assessment and therefore not reported here. Analyses of NRS scores for dysmenorrhea, NMPP, and EHP-30 pain domain score were carried out in the subgroups of patients with time since diagnosis of &amp;lt; 5 years (N = 579) and ≥5 years (N = 255). Main results and the role of chance Baseline demographics and clinical characteristics were comparable between the time since diagnosis subgroups except for a numerically higher mean age in the ≥5-years subgroup. Mean time since diagnosis (standard deviation) was 2.1 (1.5) years with both Relugolix-CT and placebo for &amp;lt;5-years subgroup, and 8.0 (2.8) and 7.8 (2.3) years, respectively, for ≥5-years subgroup. In Relugolix-CT-treated patients, mean NRS score for dysmenorrhea decreased from 7.5 (severe) to 1.8 (mild) in the &amp;lt;5-years subgroup and from 6.9 (moderate) to 1.8 (mild) in the ≥5-years subgroup with a significant difference to placebo (p &amp;lt; 0.0001, both subgroups), and demonstrating 74.8% and 72.7% reduction in pain from baseline to Week 24/EoT, respectively. Mean NRS score for NMPP decreased from 6.0 (moderate) to 3.0 (mild) with a significant difference compared with placebo (p &amp;lt; 0.0001), equating to 48.8% pain reduction in the &amp;lt;5-years subgroup, and from 5.6 (moderate) to 2.7 (mild) equating to 51.5% pain reduction (p = 0.089) in the ≥5-years subgroup. Improvement of daily functioning as measured by EHP-30 pain domain score was significantly greater with Relugolix-CT vs placebo in both subgroups, with decrease in EHP-30 pain score from 59.1 to 24.0 in the &amp;lt;5-years subgroup, and from 57.4 to 21.1 in the ≥5-years subgroup (p &amp;lt; 0.0001, both subgroups). Limitations, reasons for caution A lower number of patients were included into the subgroup with ≥5-years since surgically diagnosed endometriosis. Five-year dichotomy was close to the mean time since surgical diagnosis in the studies and to certain extent is arbitrary. Furthermore, time since surgical diagnosis is not the same as time since symptom onset. Wider implications of the findings In women with endometriosis-associated pain, Relugolix-CT vs placebo significantly reduced dysmenorrhea and improved daily functioning in both groups: with surgical diagnosis of &amp;lt; 5 years or ≥ 5 years. Substantial decrease in NMPP was also observed and was significantly different to placebo in the &amp;lt;5-years subgroup. Trial registration number NCT03204318 and NCT03204331

O-132 Sustained efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT 52-week data

Abstract Study question To assess the long-term (52-week) efficacy and safety of relugolix combination therapy (Relugolix-CT) in the treatment of endometriosis-associated pain. Summary answer Relugolix-CT demonstrated a sustained improvement of endometriosis-associated pain and maintenance of bone mineral density (BMD) over the extension treatment period. It was well tolerated. What is known already Endometriosis is a chronic condition characterized by symptoms of menstrual and non-menstrual pain, and dyspareunia, which have a substantial impact on women’s lives. SPIRIT 1 and 2 were Phase 3, randomized, double-blind, placebo-controlled studies of once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) in premenopausal women (age 18–50 years) with surgically diagnosed endometriosis and moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP) at baseline. These trials demonstrated a significant improvement of dysmenorrhea, NMPP and dyspareunia in women treated with Relugolix-CT, with a minimal decline in BMD vs placebo over 24 weeks. Study design, size, duration Women who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials) were eligible to enroll in an open-label, single-arm, long-term safety and efficacy extension study for an additional 80 weeks. All women received once-daily oral Relugolix-CT. Analyses were done based on original randomization in pivotal studies: Relugolix-CT, delayed Relugolix-CT (relugolix 40 mg alone for 12 weeks, then Relugolix-CT for 12 weeks), or placebo. Here, 52-week efficacy and safety outcomes are presented. Participants/materials, setting, methods The primary endpoints were the proportion of dysmenorrhea and NMPP responders at Week 52, based on daily Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable). A responder was a woman who achieved a predefined, clinically meaningful reduction from baseline in NRS score with no increase in analgesic use. Secondary efficacy endpoints included change in Endometriosis Health Profile-30 (EHP-30) pain domain scores, and analgesic/opioid use. Safety endpoints included adverse events (AEs) and BMD evaluation. Main results and the role of chance Of 1261 randomized patients, 1044 completed the primary studies; 802 enrolled in the long-term extension and 681 completed 52 weeks of treatment. Baseline demographics and clinical characteristics of the extension population were consistent with those of the original randomized population. Sustained improvement of endometriosis-associated pain was demonstrated with Relugolix-CT through 52 weeks, the proportion of responders for dysmenorrhea was 84.8% and 73.3% for NMPP. NRS least squares (LS) mean scores for dysmenorrhea and NMPP decreased from 7.4 (severe) and 6.0 (moderate) at SPIRIT study baseline to 1.3 (mild) and 2.2 (mild) at Week 52, equating to 82.8% and 62.9% reduction in dysmenorrhea and NMPP, respectively. Mean NRS for dyspareunia decreased from 5.9 (moderate) to 2.4 (mild), demonstrating 60.1% reduction with Relugolix-CT. Daily functioning measured by the EHP-30 pain domain score was improved (–38.1 point) and the majority of women (85.6%) were opioid-free at Week 52. There was no disproportionate increase in the incidence of AEs in the Relugolix-CT group with no new safety signals identified through the 52 weeks. BMD was preserved over the extension period with overall LS mean change from baseline to Week 52 of –0.83% (95% CI: –1.34, –0.32) for lumbar spine in the Relugolix-CT group. Limitations, reasons for caution The study was conducted as an open-label study without a control group over the 28 weeks of the extension period. Wider implications of the findings Relugolix-CT demonstrated a sustained improvement of dysmenorrhea, NMPP, and dyspareunia, and reduced pain-related functional limitations and the need for opioids over 52 weeks in women with moderate-to-severe endometriosis-associated pain. Relugolix-CT was generally well tolerated and associated with minimal BMD loss after treatment initiation followed by BMD maintenance over 52 weeks. Trial registration number NCT03654274

O-135 Long term secondary efficacy of linzagolix for heavy menstrual bleeding (HMB) due to uterine fibroids (UF): 52-week results from two placebo-controlled, randomized, phase 3 trials

Abstract Study question Are symptomatic improvements in women with UF observed after 24 weeks of linzagolix treatment with or without add-back therapy (ABT) maintained over 52 weeks? Summary answer Improvements in anemia, pain and quality of life previously reported at 24 weeks were maintained at 52 weeks. What is known already We previously reported that partial or full suppression of estradiol (E2) with once daily doses of either 100 or 200 mg linzagolix for 24 weeks, with or without ABT, were effective in reducing heavy menstrual bleeding associated with uterine fibroids, improving other symptoms such as pain and anemia and improving quality of life. Here we report the maintenance of effect on secondary endpoints after 52 weeks of treatment. Study design, size, duration Linzagolix is an investigational, oral GnRH antagonist being developed to treat HMB due to UF. PRIMROSE 1 (P1, USA, NCT03070899) and PRIMROSE 2 (P2, Europe and USA, NCT03070951) are randomized, double-blind, placebo-controlled Phase 3 trials, with essentially identical design, investigating the efficacy and safety of linzagolix with and without hormonal add-back therapy (ABT: 1 mg estradiol/0.5 mg norethindrone acetate) once daily for 52 weeks. Participants/materials, setting, methods Participants had HMB due to UF (&amp;gt;80mL menstrual blood loss (MBL)/cycle) and were equally randomized to: placebo, linzagolix 100mg, linzagolix 100mg+ABT, linzagolix 200mg, or linzagolix 200mg+ABT. After 24 weeks, subjects originally randomized to placebo or linzagolix 200mg were switched to linzagolix 200mg+ABT except in P1 where 50% placebo subjects continued placebo until 52 weeks. Secondary efficacy assessments included hemoglobin, pain (0–10 numeric rating scale) and health related quality of life (HRQL) on the UF-QoL questionnaire. Main results and the role of chance P1 trial subjects (n = 526) had a mean age of 42 years, pain score of 6.6 and HRQL total score (0–100) of 36.4 and 63% were Black. P2 trial subjects (n = 511) had a mean age of 43 years, pain score 4.8 and HRQL total score of 46.1 and 5% were Black. Mean baseline MBL was about 200 mL per cycle in both studies. In both trials, significant improvements compared to placebo observed at week 24 for secondary endpoints, including pain, anemia and QoL in all linzagolix treatment groups were maintained at 52 weeks. Mean±SD hemoglobin levels in anemic patients (&amp;lt;12 g/dL) increased from baseline by 1.7±1.9, 1.9±1.7, 2.2±2.4, 2.7±1.9 in P1 and 1.2±1.9, 2.9±1.8, 2.4±2.1, 3.0±1.4 in P2 in the 100mg, 100mg+ABT, 200mg/200mg+ABT, 200mg+ABT groups, respectively, compared to 0.6±1.8 with placebo (P1). Mean±SD change from baseline in pain scores were -3.3±3.1, -2.7±3.2, -2.6±3.0, -3.9±3.2 in P1 and -2.6±3.1, -2.6±2.8, -3.0±2.6, -2.8±3.0 in P2 in the 100mg, 100mg+ABT, 200mg/200mg+ABT, 200mg+ABT groups, respectively, compared to -0.4±2.5 with placebo (P1). Mean±SD change in HRQL total scores were 25.0±26.2, 34.2±30.1, 29.7±29.2, 38.3±29.2 in P1 and 16.8±24.0, 29.6±23.2, 31.9±26.8, 30.7±26.0 in P2 in the 100mg, 100mg+ABT, 200mg/200mg+ABT, 200mg+ABT groups, respectively, compared to 14.6±23.9 with placebo (P1). Limitations, reasons for caution Here we report data in both trials up to 52 weeks of treatment. No statistical comparisons were done at 52 weeks (the primary analysis was done after 24 weeks treatment). Post-treatment follow-up will provide more information in symptom recurrence after stopping treatment. Wider implications of the findings All linzagolix treatments provided sustained benefit. Two regimens previously identified for potential long-term treatment, 200mg with ABT and 100mg without ABT, provided sustained improvements of anemia, pain and associated quality of life. These different treatment regimens could be important to address the diverse needs of women suffering from uterine fibroids. Trial registration number ClinicalTrials.gov: NCT03070899, NCT03070951

O-136 Once-daily relugolix combination therapy results in sustained reduction in symptoms and improved quality of life in women with uterine fibroids treated over 52 weeks

Abstract Study question What is the effect of relugolix combination therapy (Relugolix-CT) on symptom burden and health-related quality-of-life (HR-QoL) in patients with uterine fibroids (UF) over 52 weeks? Summary answer Relugolix-CT demonstrated sustained, clinically meaningful improvement in patient-reported symptom severity and HR-QoL over 52 weeks in women with UF. What is known already In LIBERTY 1 and 2 randomized clinical trials, once-daily Relugolix-CT (40 mg relugolix, an oral gonadotropin-releasing hormone receptor antagonist, estradiol 1 mg, norethindrone acetate 0.5 mg) significantly reduced menstrual blood loss (MBL) and UF-associated pain versus placebo in women with UF and heavy menstrual bleeding (HMB), and was well tolerated, with bone mineral density (BMD) preservation through 24 weeks. In the LIBERTY long-term extension study, a sustained reduction in MBL was observed along with no new safety signals and BMD maintenance through 52 weeks. Relugolix-CT was previously shown to significantly improve patient-reported symptom severity and HR-QoL through 24 weeks. Study design, size, duration In the LIBERTY 1 and 2 studies, 770 premenopausal women with ultrasound-documented clinically significant UF and alkaline-hematin documented HMB were randomized 1:1:1 to Relugolix-CT for 24 weeks, relugolix 40 mg for 12 weeks followed by Relugolix-CT for 12 weeks, or placebo for 24 weeks. Women who completed the pivotal studies were eligible to enroll in the 28-week extension study (N = 477 enrolled). Patients included in the extension study received open-label once-daily Relugolix-CT. Participants/materials, setting, methods Changes from baseline to Weeks 24 and 52 in the Uterine Fibroid Symptom (UFS)-QoL symptom severity scale, Bleeding and Pelvic Discomfort scale (BPD; assessing distress due to HMB, passing blood clots, pelvic pressure/tightness); and HR-QoL (sub)scales were assessed. Higher symptom severity and BPD scores reflect higher severity and distress, respectively; higher HR-QoL scores indicate better outcomes. Least-squares mean changes were provided for the original pivotal-study randomized treatment groups Relugolix-CT and placebo. Main results and the role of chance A sustained improvement in symptom severity was observed for the Relugolix-CT group from baseline to Weeks 24 and 52, with LS mean changes of –36.9 and –37.3 points, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (–10.8 points), whereas a greater reduction from baseline was demonstrated at Week 52 (–35.0 points) after transitioning to Relugolix-CT. Considering the BPD, measuring distress from key UF symptoms, LS mean changes of –50.9 and –51.3 points were observed in the Relugolix-CT group from baseline to Week 24 and 52, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (–15.9 points), whereas a greater reduction from baseline was demonstrated at Week 52 (–48.6 points) after transitioning to Relugolix-CT. Treatment with Relugolix-CT also resulted in a sustained improvement in different aspects of HR-QoL. LS mean total HR-QoL score increased from baseline to Weeks 24 and 52 by 40.8 and 40.4 points, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (11.4 points), whereas a greater increase from baseline was demonstrated at Week 52 (39.0 points) after transitioning to Relugolix-CT at Week 24. Limitations, reasons for caution The 28-week LIBERTY long-term extension study was non-comparative. Analyses were performed in a subset of patients who completed the LIBERTY pivotal studies and were eligible for the extension study. However, it is important to note that the demographic and baseline disease characteristics were similar between pivotal and long-term extension populations. Wider implications of the findings Relugolix-CT resulted in a sustained reduction in UF symptom burden, particularly in terms of distress from key UF symptoms, and a sustained improvement of HR-QoL over 52 weeks. Improvements observed after transitioning from placebo to Relugolix-CT at 24 weeks confirmed the positive effect of Relugolix-CT on UF-associated symptoms and HR-QoL. Trial registration number NCT03412890

Nonhormonal therapy for endometriosis: a randomized, placebo-controlled, pilot study of cabergoline versus norethindrone acetate

ObjectiveTo estimate the efficacy and safety of a novel nonhormonal therapeutic agent, cabergoline, compared with that of the standard clinical therapy, norethindrone acetate (NETA), for the treatment of endometriosis-associated pain in young women with endometriosis.DesignRandomized, double-blind, placebo-controlled pilot study.SettingTertiary care center.Patient(s)Women (n = 9) with surgically confirmed endometriosis.Intervention(s)A random, double-blind assignment to either NETA (5 mg/day) + placebo twice weekly or cabergoline (0.5 mg) twice weekly + placebo daily for 6 months.Main Outcome Measure(s)We collected the measures of pelvic pain and laboratory parameters every 3 months.Result(s)We observed a decrease in pain scores and increase in pain relief in women randomized to receive cabergoline, who appeared to show similar or more improvements than women treated with NETA. The serum measures of vascular endothelial growth factor receptor 1 declined over 6 months in those who received cabergoline. Cabergoline was well tolerated, and no serious adverse events occurred.Conclusion(s)Safe, effective adjunct treatments are lacking for patients with endometriosis who do not respond to standard care. Because the growth of endometriosis requires angiogenesis, blood vessel growth is an attractive therapeutic target. This pilot study suggests that cabergoline, a vascular endothelial growth factor pathway inhibitor, is an effective therapeutic option for women with chronic pain due to endometriosis. Building upon this investigation, we will conduct larger, randomized trials of cabergoline, advancing research on the best treatments for endometriosis—particularly disease resistant to hormonal therapies.Clinical Trial Registration Numberclinicaltrials.gov; registration number NCT02542410.

Oriahnn: New Drug Approved for Treating Heavy Menstrual Bleeding in Women With Uterine Fibroids.

To review data of elagolix plus estradiol and norethindrone acetate as add-back therapy for the treatment of heavy menstrual bleeding (HMB) in premenopausal women with uterine fibroids. Literature search of PubMed/MEDLINE and SCOPUS was performed using the search terms Oriahnn; elagolix, estradiol, norethindrone AND heavy menstrual bleeding; elagolix AND heavy menstrual bleeding; and gonadotropin-releasing hormone receptor antagonist AND heavy menstrual bleeding between January 1, 1996, to March 2, 2021. Additional data were obtained from prescribing information, references of identified articles, and abstracts from scientific meetings. Clinical trials and articles discussing elagolix plus add-back therapy for the management of HMB in women with leiomyomas were included. Phase 3 trials met the primary end point of menstrual blood loss (MBL) less than 80 mL at month 6 and at least a 50% reduction in MBL from baseline to the final month in 68.5% of women taking elagolix plus add-back therapy enrolled in UF-1 (8.7% placebo) and 76.5% of women in UF-2 (10% placebo). The most common adverse effects include hot flushes, nausea, headache, and night sweats. Women with symptomatic uterine fibroids can experience significant HMB resulting in distress, depression, and anxiety. Surgical intervention remains the most commonly recommended and chosen treatment. Elagolix plus add-back therapy is a nonsurgical, oral option. Elagolix plus add-back therapy is effective in reducing menstrual bleeding associated with uterine fibroids. However, there are several warnings and precautions that must be considered.

24. Peri-urethral cyst mistaken for imperforate hymen in a patient with distal vaginal agenesis

<h3>Background</h3> Imperforate hymen is the most common obstructive genital tract anomaly and typically presents in adolescence with primary amenorrhea, worsening pelvic pain, and a bulging hymenal membrane at the introitus. When the hymen is normally visualized, other obstructive anomalies should be considered, as establishing the correct diagnosis prior to making management decisions is paramount. We present a case of a peri-urethral cyst misdiagnosed as an imperforate hymen in a patient with vaginal agenesis, highlighting strategies for accurate diagnosis and options for management. <h3>Case</h3> An 11 year old premenarchal female presented to the Emergency Department (ED) with several months of worsening intermittent lower abdominal pain. In the ED, she had transabdominal pelvic imaging showing a large hematometrocolpos and per the provider an imperforate hymen external genital exam. After achieving adequate pain control, she was discharged to follow up with Pediatric and Adolescent Gynecology. At her follow up visit, examination findings were notable for an annular hymen with membranous tissue blocking the vagina immediately behind the hymen. On rectal exam, the hematocolpos was palpated approximately 4 cm from the introitus. The patient was started on menstrual suppression with depot leuprolide and norethindrone acetate. Follow up magnetic resonance imaging (MRI) confirmed a cyst near the introitus and distal vaginal agenesis. When the genitalia were re-examined under anesthesia, adequate labial traction revealed a peri-urethral cyst. Due to ongoing pain, interventional radiology placed a transuterine drain under ultrasound guidance. Tissue plasminogen activator (TPA) was used through the drain to thin the obstructed blood and facilitate drainage. Approximately 500 ml of blood was drained from uterus and vagina before the drain was removed. The patient remains asymptomatic and will continue menstrual suppression until she reaches an age when she can participate in post-operative care. <h3>Comments</h3> In this case, the diagnosis of distal vaginal agenesis was obscured by the presence of a peri-urethral cyst. The case illustrates the importance of thorough examination including rectal exam and pelvic MRI when the diagnosis is unclear. Vaginal dilation or use of a vaginal stent is usually required after definitive surgical management of distal vaginal agenesis and therefore it is important to consider age and maturity before any surgical decisions are made. Accurate diagnosis is of utmost importance and management efforts aimed at delaying definitive surgical management should be considered.