Relugolix/Estradiol/Norethisterone Acetate: A Review in Endometriosis-Associated Pain.

An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate [Myfembree® (USA); Ryeqo® (EU)] (hereafter referred to as relugolix combination therapy) has been approved in the USA for the management of moderate to severe pain associated with endometriosis in premenopausal women and in the EU for the symptomatic treatment of endometriosis in adult women of reproductive age with a history of previous medical or surgical treatment for their endometriosis. The gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix decreases estradiol and progesterone levels, while the addition of estradiol/norethisterone acetate mitigates hypoestrogenic effects including bone mineral density (BMD) loss and vasomotor symptoms. In two pivotal phase III trials, relugolix combination therapy significantly improved dysmenorrhoea and non-menstrual pelvic pain in premenopausal women with moderate to severe endometriosis. The combination also reduced overall pelvic pain and dyspareunia, reduced analgesic and opioid use, and improved health-related quality of life. The efficacy of relugolix combination therapy was sustained over the longer term (up to 2 years). Relugolix combination therapy was generally well tolerated and BMD loss over time was minimal. With the convenience of a once daily oral dosing regimen, relugolix combination therapy is a valuable addition to the options currently available for the management of endometriosis-associated pain.

Endometriosis is a disease where tissue similar to the lining of the uterus grows outside the uterus and may reach other organs. This causes chronic pain as a result of increased inflammation and scar tissue. Women with endometriosis may experience painful menstrual periods, pelvic pain between periods, pain during sex, painful bowel movements and painful urination. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone (also known as norethindrone) acetate [Myfembree^® (USA); Ryeqo^® (EU)] (hereafter referred to as relugolix combination therapy) has been approved to treat endometriosis-associated pain. The treatment works by decreasing levels of ovarian hormones (estrogen and progesterone). In clinical trials, relugolix combination therapy improved period pain and pain between periods in women with moderate to severe pain associated with endometriosis. The treatment also improved other symptoms (overall pelvic pain and pain during sex), reduced the need for pain medications and improved health-related quality of life. Relugolix combination therapy was generally well tolerated and caused minimal bone loss, which is known to occur with some hormone therapies. With the convenience of a once daily oral pill, relugolix combination therapy is a valuable addition to the options currently available for women with endometriosis-associated pain.

Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women.

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.

Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3).

STUDY QUESTION: Does linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone or 200 mg in combination with add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethindrone acetate, also known as norethisterone acetate [NETA]) demonstrate better efficacy than placebo in the management of endometriosis-related dysmenorrhea and non-menstrual pelvic pain? SUMMARY ANSWER: Combining 200 mg linzagolix with ABT was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain at 3 months of therapy, while a daily dose of 75 mg linzagolix yielded a significant decrease only in dysmenorrhea at 3 months. WHAT IS KNOWN ALREADY?: A previously published Phase 2, dose-finding study reported that at a dose of 200 mg daily, linzagolix promotes full suppression of estradiol secretion to serum levels below 20 pg/ml and noted that the addition of ABT may be needed to manage hypoestrogenic side effects. At lower doses (75 mg and 100 mg/day), linzagolix maintains estradiol values within the target range of 20-60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis. STUDY DESIGN, SIZE, DURATION: EDELWEISS 3 was a multicenter, prospective, randomized, placebo-controlled, double-blind, double-dummy Phase 3 study to evaluate the safety and efficacy of linzagolix for the treatment of moderate-to-severe endometriosis-associated pain. Treatment was administered orally once daily for up to 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the EDELWEISS 3 trial, 486 subjects with moderate-to-severe endometriosis-associated pain were randomized at a 1:1:1 ratio to one of the three study groups: placebo, 75 mg linzagolix alone or 200 mg linzagolix in association with ABT. Pain was measured daily on a verbal rating scale and recorded in an electronic diary. MAIN RESULTS AND THE ROLE OF CHANCE: At 3 months, the daily 200 mg linzagolix dose with ABT met the primary efficacy objective, showing clinically meaningful and statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain, with stable or decreased use of analgesics. The proportion of responders for dysmenorrhea in the 200 mg linzagolix with ABT group was 72.9% compared with 23.5% in the placebo group (P < 0.001), while the rates of responders for non-menstrual pelvic pain were 47.3% and 30.9% (P = 0.007), respectively. The 75 mg linzagolix daily dose demonstrated a clinically meaningful and statistically significant reduction in dysmenorrhea versus placebo at 3 months. The proportion of responders for dysmenorrhea in the 75 mg linzagolix group was 44.0% compared with 23.5% in the placebo group (P < 0.001). Although the 75 mg dose showed a trend toward reduction in non-menstrual pelvic pain at 3 months relative to the placebo, it was not statistically significant (P = 0.279). Significant improvements in dyschezia and overall pelvic pain were observed in both linzagolix groups when compared to placebo. Small improvements in dyspareunia scores were observed in both linzagolix groups but they were not significant. In both groups, hypoestrogenic effects were mild, with low rates of hot flushes and bone density loss of <1%. A daily dose of 200 mg linzagolix with ABT or 75 mg linzagolix alone was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain also at 6 months of therapy. LIMITATIONS, REASONS FOR CAUTION: Efficacy was compared between linzagolix groups and placebo; however, it would be useful to have results from comparative studies with estro-progestogens or progestogens. It will be important to ascertain whether gonadotropin-releasing hormone antagonists have significant benefits over traditional first-line medications. WIDER IMPLICATIONS OF THE FINDINGS: Linzagolix administered orally once daily at a dose of 200 mg in combination with add-back therapy (ABT) demonstrated better efficacy and safety than placebo in the management of moderate-to-severe endometriosis-associated pain. The quality of life was improved and the risks of bone loss and vasomotor symptoms were minimized due to the ABT. The 75 mg dose alone could be suitable for chronic treatment of endometriosis-associated pain without the need for concomitant hormonal ABT, but further research is needed to confirm this. If confirmed, it would offer a viable option for women who do not want to wish to have ABT or for whom it is contraindicated. STUDY FUNDING/COMPETING INTEREST(S): Funding for the EDELWEISS 3 study was provided by ObsEva (Geneva, Switzerland). Analysis of data and manuscript writing were partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK) and Kissei (Japan) and grant 5/4/150/5 was awarded to M.-M.D. by FNRS. J.D. was a member of the scientific advisory board of ObsEva until August 2022, a member of the scientific advisory board of PregLem, and received personal fees from Gedeon Richter, ObsEva and Theramex. J.D. received consulting fees, speakers' fees, and travel support from Gedeon Richter, Obseva and Theramex, which was paid to their institution. C.B. has received fees from Theramex, Gedeon Richter, and Myovant, and travel support from Gedeon Richter-all funds went to the University of Oxford. He was a member of the data monitoring board supervising the current study, and served at an advisory board for endometriosis studies of Myovant. H.T. has received grants from Abbvie and was past president of ASRM. F.C.H. has received fees from Gedeon Richter and Theramex. O.D. received fees for lectures from Gedeon Richter and ObsEva and research grants for clinical studies from Preglem and ObsEva independent from the current study. A.H. has received grants from NIHR, UKRI, CSO, Wellbeing of Women, and Roche Diagnostics; he has received fees from Theramex. A.H.'s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta, and Joii. M.P. has nothing to declare. F.P. has received fees from Theramex. S.P.R. has been a member of the scientific advisory board of Gedeon Richter and received fees from Gedeon Richter. A.P. and M.B. are employees of Theramex. E.B. was an employee of ObsEva, sponsor chair of the data monitoring board supervising the current study, and has been working as a consultant for Theramex since December 2022; she owns stock options in ObsEva. M.-M.D. has received fees and travel support from Gedeon Richter and Theramex. TRIAL REGISTRATION NUMBER: NCT03992846. TRIAL REGISTRATION DATE: 20 June 2019. DATE OF FIRST PATIENT'S ENROLLMENT: 13 June 2019.

Oocyte competence is comparable between progestin primed ovarian stimulation with Norethisterone acetate (NETA-PPOS) and GnRH-antagonist protocols: A matched case-control study in PGT-A cycles.

OBJECTIVE: To outline oocyte competence after progestin primed ovarian stimulation with Norethisterone acetate (NETA-PPOS) compared to conventional GnRH-antagonist protocol. STUDY DESIGN: Retrospective matched case-control study involving advanced-maternal-age women undergoing ICSI with PGT-A. 89 NETA-PPOS were matched with 178 control patients based on maternal age and ovarian reserve biomarkers. Both groups underwent recombinant-FSH OS with GnRH-agonist ovulation trigger and collected ≥1 MII. In the study group, NETA (10 mg/day) was administered orally starting from day2 of the menstrual cycle. Euploid blastocyst rate per cohort of metaphase-II oocytes (EBR per MII) was the primary outcome. All other embryological and clinical outcomes were reported. Gestational age, birthweight and length were also assessed. RESULTS: The EBR per MII was comparable among PPOS and control (13.9 % ± 19.3 % versus 13.3 % ± 17.9 %; the sample size allowed to exclude up to a 10 % difference). Blastocysts morphology and developmental rate were similar. No difference was reported for all clinical outcomes among the 61 and 107 vitrified-warmed euploid single blastocyst transfers respectively conducted. The cumulative live birth delivery rate per concluded cycles was also comparable (24.7 % versus 21.9 %). Neonatal outcomes were analogous. CONCLUSIONS: Oocyte competence after NETA-PPOS and standard OS is comparable. This evidence is reassuring and, because of its lower cost and possibly higher patients' compliance, supports PPOS administration whenever the patients are indicated to freeze-all (e.g., fertility preservation, PGT-A, oocyte donation). More data are required about follicle recruitment, oocyte yield, gestational and perinatal outcomes. Randomized-controlled-trials are advisable to confirm our evidence.

Medical Management of Ovarian Endometriomas: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the effect of medical management on the size of ovarian endometriomas. DATA SOURCE: Online databases were searched from inception to October 2022, including Ovid MEDLINE, Ovid EMBASE, PubMed, EBM Reviews-Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov , and Web of Science. METHODS OF STUDY SELECTION: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we included all English-language, full-text articles that reported on change in endometrioma size (either diameter or volume) after medical interventions. Studies evaluating surgical interventions or postoperative recurrence were excluded. All screening and data extraction were performed independently by two authors. Risk of bias assessment was performed with either the Cochrane Risk of Bias Tool for randomized controlled trials or a modified Newcastle-Ottawa Scale for observational studies. TABULATION, INTEGRATION, AND RESULTS: After removal of duplicates, 9,332 studies were screened, with 33 full-text articles deemed eligible for inclusion. In the meta-analysis, dienogest showed significant reduction in cyst diameter (reduction 1.32 cm, 95% CI, 0.91-1.73, eight studies, n=418 cysts) and volume (mean difference of log-transformed volume 1.35, 95% CI, 0.87-1.83, seven studies, n=282 cysts). Similarly, significant reductions were seen with the oral contraceptive pill (OCP) (1.06 cm, 95% CI, 0.59-1.53, nine studies, n=455), gonadotropin-releasing hormone (GnRH) agonists (1.17 cm, 95% CI, 0.42-1.92, four studies, n=128 cysts), norethindrone acetate (0.6 cm, 95% CI, 0.27-0.94, two studies, n=88 cysts), and danazol (1.95 cm, 95% CI, 1.18-2.73, two studies, n=34 cysts). Norethindrone acetate with aromatase inhibitor was also effective in reducing endometrioma volume (mean difference of log-transformed volume 1.47, 95% CI, 0.16-2.78, two studies, n=34 cysts). CONCLUSION: Medical management with dienogest, OCPs, GnRH agonists, norethindrone acetate, norethindrone acetate with aromatase inhibitor, or danazol can reduce the size of ovarian endometriomas. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD 42022363319.

Effects of Transdermal 17ß-Estradiol + Norethisterone Acetate on Cardiovascular Disease Risk Factors in Postmenopausal Women: A Meta-analysis of Data From Randomized, Controlled Trials.

PURPOSE: To date, no study has demonstrated the role of transdermal 17ß-estradiol + norethisterone acetate on all of the risk factors for cardiovascular disease in postmenopausal women. To overcome this knowledge gap, a systematic review and meta-analysis were conducted to determine the effects of this combination treatment on BMI, body weight, waist/hip ratio, fibrinogen, factor VII, lipoprotein(a), fasting blood sugar, insulin, HbA1c, TG, LDL-C, HDL-C, and TC in postmenopausal women. METHODS: PubMed/Medline, SCOPUS, Web of Science, Embase, and Google Scholar were searched for relevant articles published between the inception of each database and April 6, 2023. The sample size and mean (SD) were used to calculate overall effect size using a random-effects model. FINDINGS: A total of 10 articles with 14 arms were included in the meta-analysis. On pooled analysis of effect size, fibrinogen (weighted mean difference [WMD], -0.18 g/L; 95% CI, -0.25 to -0.10), factor VII (WMD, -9.58; 95% CI, -12.51 to -6.64), LDL-C (WMD, -13.09 mg/dL; 95% CI, -18.48 to -7.71), and TC (WMD, -12.61 mg/dL; 95% CI, -18.11 to -7.12) were significantly affected with the use of transdermal 17ß-estradiol + norethisterone acetate (all, P < 0.001), but effects on lipoprotein(a), TG, HDL-C, fasting blood sugar, insulin, HbA1c, BMI, body weight, and waist/hip ratio were not significant. IMPLICATIONS: Based on the findings from the present systematic review and meta-analysis, it was concluded that transdermal administration of 17ß-estradiol + norethisterone acetate had beneficial impacts on fibrinogen, factor VII, LDL-C, and TC, suggesting a possible application in the reduction of cardiovascular disease risk.

Norethindrone dosing for adequate menstrual suppression in adolescents.

OBJECTIVES: We sought to study factors predictive of achieving menstrual suppression with norethindrone vs. norethindrone acetate in adolescents, as optimal dosing is unknown. Secondary outcomes included analyzing prescriber practices and patient satisfaction. METHODS: We performed a retrospective chart review of adolescents ages <18 years presenting to an academic medical center from 2010 to 2022. Data collected included demographics, menstrual history, and norethindrone and norethindrone acetate use. Follow-up was measured at one, three, and 12 months. Main outcome measures were starting norethindrone 0.35 mg, continuing norethindrone 0.35 mg, achieving menstrual suppression, and patient satisfaction. Analysis included Chi-square and multivariate logistic regression. RESULTS: Of 262 adolescents initiating norethindrone or norethindrone acetate, 219 completed ≥1 follow-up. Providers less often started norethindrone 0.35 mg for patients with body mass index ≥25 kg/m2, prolonged bleeding, or younger age at menarche, but more often for patients who were younger, had migraines with aura, or were at risk of venous thromboembolism. Those with prolonged bleeding or older age at menarche were less likely to continue norethindrone 0.35 mg. Obesity, heavy menstrual bleeding, and younger age were negatively associated with achieving menstrual suppression. Patients with disabilities reported greater satisfaction. CONCLUSIONS: While younger patients more often received norethindrone 0.35 mg vs. norethindrone acetate, they were less likely to achieve menstrual suppression. Patients with obesity or heavy menstrual bleeding may achieve suppression with higher doses of norethindrone acetate. These results reveal opportunities to improve norethindrone and norethindrone acetate prescribing practices for adolescent menstrual suppression.

The influence of 17ß-estradiol plus norethisterone acetate treatment on markers of glucose and insulin metabolism in women: a systematic review and meta-analysis of randomized controlled trials.

Objective: Despite the fact that some evidence suggests that the administration of 17ß-estradiol plus norethisterone acetate influences glucose and insulin metabolism in women, these findings are still contradictory. Thus, we aimed to examine the impact of the co-administration of 17ß-estradiol and norethisterone acetate on glycated haemoglobin (HbA1c), fasting glucose, insulin and C-peptide concentrations in females by means of a systematic review and meta-analysis of randomized controlled trials (RCTs). Methods: We searched four databases (PubMed/MEDLINE, Scopus, Embase, and Web of Science) using specific keywords and word combinations. The random-effects model (DerSimonian and Laird model) was employed to compute the weighted mean difference (WMD) and 95% confidence intervals (CIs) for the variations from baseline of HbA1c, fasting glucose, insulin, and C-peptide concentrations. Results: In total, 14 RCTs were entered into the quantitative synthesis. The combined administration of 17ß-estradiol and norethisterone acetate decreased HbA1c (WMD: -0.65%, 95% CI: -1.15 to -0.15; P=0.011), fasting glucose (WMD: -11.05 mg/dL, 95% CI: -16.6 to -5.5; P<0.001) and insulin (WMD: -1.35 mIU/L, 95% CI: -2.20 to -0.50; P=0.001) levels. C-peptide concentrations' declined only in females diagnosed with overweight/obesity or diabetes. Conclusion: Evidence to date points out that the administration of 17ß-estradiol and norethisterone acetate has a positive impact on glucose metabolism in women by reducing fasting glucose, HbA1c, and insulin values. Future studies need to confirm the potential benefits of this drug combination in the prevention and/or management of cardiometabolic disorders.

The effect of 17beta-estradiol plus norethisterone acetate on anthropometric indices: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Little evidence exists on the effect of 17beta-estradiol plus norethisterone acetate on all the anthropometric indices. Hence, this systematic review and meta-analysis of Randomized Controlled Trials was conducted to give an evidence-based report on the effect of 17beta-estradiol plus norethisterone acetate on anthropometric indices. METHODS: The literature search was executed in databases including PubMed/Medline, Web of Science, Scopus, Embase, and Google Scholar to recognize clinical trials that examined the influence of 17beta-estradiol plus norethisterone acetate on obesity indices from database inception to Jan 2023. RESULTS: Combined findings were generated from 20 eligible articles. The meta-analysis showed that body weight (Weighted Mean Difference (WMD): -0.47 kg, 95% CI: -1.32, 0.37, p = 0.274), body fat (WMD: 0.16 kg, 95% CI: -1.26, 1.59, p = 0.821), WHR (WMD: 0.001 kg, 95% CI: -0.006, 1.15, p = 0.872), and LBM (WMD: -0.02 kg, 95% CI: -1.19, 1.15, p = 0.970) were not modified in DHEA group compared to the control, but BMI levels were significantly reduced in 17beta-estradiol plus norethisterone acetate group (WMD: -0.15 kg/m2, 95% CI: -0.30, -0.008, p = 0.039). Moreover, based on intervention duration (months), a more significant reduction in BMI was found in trials that were performed on studies with ˃3 months duration (WMD: -0.176 kg/m2) than studies with ≤ 3 months (WMD: 0.05 kg/m2). CONCLUSION: Administration of 17beta-estradiol plus norethisterone acetate for more than 3 months results in a decrease in BMI, which helps to reduce cardiovascular disease risk.

A Randomized Open-Label Study of Relugolix Alone or Relugolix Combination Therapy in Premenopausal Women.

BACKGROUND AND OBJECTIVE: Relugolix is a gonadotropin-releasing hormone receptor antagonist. Relugolix 40-mg monotherapy is associated with vasomotor symptoms and long-term bone mineral density loss due to hypoestrogenism. This study assessed whether the addition of estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg to relugolix 40 mg (relugolix combination therapy) provides systemic E2 concentrations in the 20-50 pg/mL range to minimize these undesirable effects. METHODS: This was a randomized, open-label, parallel-group study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of relugolix 40 mg alone or in combination with E2 1 mg and NETA 0.5 mg in healthy premenopausal women. Eligible women were randomized 1:1 to receive relugolix alone or relugolix plus E2/NETA for 6 weeks. Study assessments included pharmacokinetic parameters of E2, estrone, and relugolix in both treatment groups, and norethindrone in the relugolix plus E2/NETA treatment group at weeks 3 and 6. RESULTS: Median E2 24 h average concentrations with the relugolix plus E2/NETA group (N = 23) were 31.5 pg/mL, 26 pg/mL higher compared with the relugolix-alone group (6.2 pg/mL) (N = 25). There were 86.4% of participants in the relugolix plus E2/NETA group who had E2 average concentrations exceeding 20 pg/mL, the threshold expected to minimize bone mineral density loss, compared with 21.1% in the relugolix-alone group. Both treatments were generally safe and well tolerated. CONCLUSIONS: Relugolix 40 mg in combination with E2 1 mg and NETA 0.5 mg provided systemic E2 concentrations within a range expected to minimize the risk of undesirable effects of hypoestrogenism associated with the administration of relugolix alone. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier no. NCT04978688. Trial registration date: 27 July, 2021; retrospectively registered.

Dienogest versus norethisterone acetate in management of endometrial hyperplasia without atypia.

OBJECTIVES: To compare the effectiveness of dienogest (DIE) and norethisterone acetate (NETA) regimens in the treatment of endometrial hyperplasia (EH) without atypia. METHODS: Participants were premenopausal women with irregular uterine bleeding, and endometrial hyperplasia without atypia on endometrial biopsy. Enrolled patients were randomly allocated into two groups: group I got DIE 2 mg/day (orally Visanne) for 14 days (10th to the 25th day of cycle) while group II received between the 16th and 25th day of the cycle, norethisterone acetate (NETA) 15 mg/d (orally Primolut Nor) was administered for 10 days. Both groups continued the therapy for six months. RESULTS: The DIE group showed a higher resolution (32.7%) and regression (57.7%) than NETA group (31% & 37.9%, respectively) with significant regression (p = 0.039). No progression in DIE group while four (6.9%) women in NETA group were recorded a progression to complex type without a significance. Also, NETA group showed a significant persistence rate (22.5%) than DIE group (3.8%) (p = 0.005). Also number in NETA group managed by hysterectomy with significant difference (p = 0.042). CONCLUSION: If used as first-line treatment, Dienogest produces a better rate of regression and a lower incidence of hysterectomy than Norethisterone Acetate does when used in EH without atypia.

The effect of 17ß-estradiol plus norethisterone acetate on blood pressure and inflammation markers: A meta-analysis of randomized controlled trials.

OBJECTIVE: Several randomized controlled trials (RCTs) have explored the impact of 17ß-estradiol plus norethisterone acetate administration on blood pressure and inflammation markers, however, their findings have often been contradictory. Thus, we conducted a systematic review and meta-analysis of RCTs to assess the effects of this drug combination on systolic blood pressure (SBP), diastolic blood pressure (DBP) and C-reactive protein (CRP) concentrations. METHODS: The Cochrane Library, PubMed/Medline, Scopus, and Google Scholar were searched to identify relevant published RCTs. The pooled mean change and standard deviation (SD) of the outcomes were calculated using the STATA software (version 14) for Statistical Computing. RESULTS: A total of 18 publications were included in the current meta-analysis. In total, there were 12 RCT arms on SBP, 12 RCT arms on DBP, and 6 RCT arms on CRP levels. The administration of 17ß-estradiol plus norethisterone acetate intake increased SBP (WMD: 3.48 mmHg, 95% CI: 0.73, 6.23, P = 0.013), particularly in subjects aged ≥ 60 years (WMD: 5.89 mmHg, 95% CI: 1.71, 10.07, P = 0.006) or with a body mass index (BMI) < 30 kg/m2 (WMD: 6.55 mmHg, 95% CI: 2.64, 10.46, P = 0.012), as well as in the RCTs which lasted ≥ 6 months (WMD: 6.47 mmHg, 95% CI: 3.03, 9.90, P < 0.001),when 17ß-estradiol dosages were ≥ 2 mg/day (WMD: 4.12 mmHg, 95% CI: 1.03, 7.22, P = 0.009; I2 = 99%, P < 0.001) and in RCTs conducted on healthy postmenopausal women (WMD: 4.22 mmHg, 95% CI: 0.43, 8.01, P = 0.02; I2 = 94%, P < 0.001). DBP decreased following this drug combination in the RCTs which lasted < 6 months (WMD: -1.42 mmHg, 95% CI: -2.27, -0.57, P = 0.001). CRP concentrations increased following the use of this drug combination (WMD: 1.01 mg/L, 95% CI: 0.62, 1.41, P < 0.001), especially in participants aged < 60 years (WMD: 1.22 mg/L, 95% CI: 0.77, 1.68, P < 0.001) or with a BMI < 30 kg/m2 (WMD: 0.97 mg/L, 95% CI: 0.67, 1.27, P < 0.001), as well as in RCTs with a duration of ≥ 6 months (WMD: 1.15 mg/L, 95% CI: 0.57, 1.73, P < 0.001), when 17ß-estradiol dosages were ≥ 2 mg/day (WMD: 0.97 mg/L, 95% CI: 0.67, 1.27, P < 0.001; I2 = 55%, P = 0.107) and in RCTs conducted on healthy postmenopausal women (WMD: 1.22 mg/L, 95% CI: 0.77, 1.68, P < 0.001; I2 = 90%, P < 0.001). CONCLUSION: The administration of 17ß-estradiol plus norethisterone acetate increases SBP and CRP concentrations and, when prescribed for less than 6 months, decreases DBP. However, despite being statistically significant, the impact of this drug combination on SBP and DBP is not clinically relevant as the variation in blood pressure values was low.

Outcomes of Menstrual Management Use in Transgender and Gender-Diverse Adolescents.

OBJECTIVE: To describe and compare the outcomes of various menstrual-management methods, including method choice, continuation, bleeding patterns, amenorrhea rates, effect on moods and dysphoria, and side effects, in transgender and gender-diverse adolescents. METHODS: This was a retrospective chart review of all patients seen in a multidisciplinary pediatric gender program from March 2015 to December 2020 who were assigned female at birth, had achieved menarche, and used a menstrual-management method during the study period. Data were abstracted on patient demographics and menstrual-management method continuation, bleeding patterns, side effects, and satisfaction at 3 months (T1) and 1 year (T2). Outcomes were compared between method subgroups. RESULTS: Among the 101 included patients, 90% chose either oral norethindrone acetate or a 52-mg levonorgestrel (LNG) intrauterine device (IUD). There were no differences in continuation rates for these methods at either follow-up time. Almost all patients had improved bleeding at T2 (96% for norethindrone acetate and 100% for IUD users), with no difference between subgroups. Amenorrhea rates were 84% for norethindrone acetate and 67% for IUD at T1 and 97% and 89%, respectively, at T2, with no differences at either point. The majority of patients had improved pain, menstrually related moods, and menstrually related dysphoria at both follow-up points. There were no differences in side effects between subgroups. There were no differences in method satisfaction between the groups at T2. CONCLUSION: Most patients chose norethindrone acetate or an LNG IUD for menstrual management. Continuation, amenorrhea, and improved bleeding, pain, and menstrually related moods and dysphoria were high for all patients, indicating that menstrual management is a viable intervention for gender-diverse patients who experience increased dysphoria related to menses.

Efficacy and safety of ultra-low-dose estradiol and norethisterone in postmenopausal Brazilian women.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of oral ultra-low-dose continuous combination of 17ß-estradiol (17ß-E2) and norethisterone acetate (NETA) in postmenopausal Brazilian women. METHODS: Postmenopausal women (age 45-60 years) with amenorrhea >12 months and intact uterus, with moderate to severe vasomotor symptoms, were included. The vasomotor symptoms and endometrial bleeding were evaluated by a daily diary for 24 weeks, and the women were assessed at baseline and endpoint. RESULTS: A total of 118 women were included. The group treated with 0.5 mg 17ß-E2/0.1 mg NETA (n = 58) showed a percentage reduction of 77.1% in the frequency of vasomotor symptoms versus 49.9% in the placebo group (n = 60) (p = 0.0001). The severity score showed a reduction in the treatment group when compared to the placebo (p < 0.0001). The adverse events were comparable between the groups; however, in the 0.5 mg 17ß-E2/0.1 mg NETA group there were more complaints of vaginal bleeding; despite that, in most cycles in both treatment groups, more than 80% of women experienced amenorrhea. CONCLUSIONS: The combination of 0.5 mg 17ß-E2/0.1 mg NETA in a continuous combination regimen was shown to be effective in reducing the frequency and severity of vasomotor symptoms in Brazilian postmenopausal women.

Effects of norethisterone acetate on the performance of female racing Greyhounds.

A comparison between the performance of spayed female racing Greyhounds and those suppressed with norethisterone acetate (NTA) was made. Previous work by the author has shown that the racing performance of spayed bitches is the same as that of entire bitches in anoestrus, i.e. spaying is just a permanent anoestrus. The aim was to assess any performance difference between suppression and anoestrus, and thus to determine the effect of norethisterone acetate on race performance. The study was designed as a retrospective case-control. Raceform data was obtained for female racing Greyhounds which had raced, and which were either spayed or suppressed with norethisterone acetate. Analysis showed that suppressed bitches run on average 0.049 to 0.061 s slower over 480 m (centralised models). Since endogenous progesterone (P4) has been linked with reduced race performance, it is logical that progesterone analogues like NTA should have a similar effect. It is likely that the depression in performance is dose-related, but not quantifiable with the current dataset.

The effect of 17ß-estradiol plus norethisterone acetate treatment on lipoprotein (a), atherogenic and anti-atherogenic apolipoproteins levels in postmenopausal women: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: The administration of 17ß-estradiol plus norethisterone acetate seems to confer women cardioprotection, however, its impact on lipoprotein (a) and apolipoproteins' concentrations remains unclear. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) to investigate the effect of 17ß-estradiol plus norethisterone acetate treatment on lipoprotein (a) and apolipoproteins' values in females. METHODS: We systematically searched four databases (PubMed/MEDLINE, Scopus, Embase, and Web of Science) to identify relevant publications published until March 9th, 2022. No language restrictions were applied. The random-effects model (the DerSimonian and Laird methods) was employed to calculate the weighted mean difference (WMD). RESULTS: The administration of 17ß-estradiol plus norethisterone acetate resulted in a significant decrease of lipoprotein (a) (WMD: -67.59 mg/L, 95 % CI: -106.39 to -28.80; P < 0.001) and apolipoprotein B concentrations (WMD: -3.71 mg/dL, 95 % CI: -6.68 to -0.75; P = 0.014), respectively. No effect of 17ß-estradiol plus norethisterone acetate on apolipoprotein AI (WMD: 0.23 mg/dL, 95 % CI: -3.99 to 4.46; P = 0.91) or AII (WMD: 0.21 mg/dL, 95 % CI: -2.24 to 2.68; P = 0.86) concentrations was detected. In the stratified analysis, there was a notable reduction in lipoprotein (a) levels in the RCTs with a duration of ≥6 months (WMD: -73.34 mg/L), in postmenopausal women with a BMI ≥25 kg/m2 (WMD: -69.85 mg/L) and in postmenopausal women aged ˂60 years (WMD: -61.93 mg/L). CONCLUSION: The present meta-analysis of RCTs demonstrates that 17ß-estradiol plus norethisterone acetate treatment reduces lipoprotein (a) and apolipoprotein B levels in postmenopausal women.

Relugolix/Estradiol/Norethisterone (Norethindrone) Acetate: A Review in Symptomatic Uterine Fibroids.

An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate (Ryeqo®; Myfembree®) has been approved for the management of heavy menstrual bleeding associated with uterine fibroids in the USA and management of moderate to severe symptoms of uterine fibroids in the EU. Relugolix is a gonadotropin releasing hormone (GnRH) receptor antagonist that decreases serum estradiol and progesterone concentrations to postmenopausal levels. The addition of estradiol/norethisterone acetate to relugolix ameliorates relugolix-induced bone loss and hot flush. In the two phase 3 LIBERTY trials, relugolix + estradiol/norethisterone substantially decreased menstrual bleeding and improved a range of other uterine fibroid symptoms in women with uterine fibroids-associated heavy menstrual bleeding. The combination was generally well tolerated, with vasomotor symptoms being the most common adverse reaction. Treatment with this combination for over up to 2 years did not induce a clinically meaningful bone loss in the majority of women. Relugolix/estradiol/norethisterone acetate, with its convenient once-daily administration, is a useful addition to current pharmacological treatment options for premenopausal women with symptomatic uterine fibroids.

Uterine fibroids are a common type of noncancerous tumours that grow in the uterus. In some women, these tumours cause debilitating symptoms, such as heavy menstrual bleeding, pelvic pain and passing of blood clots. Hysterectomy is the only definitive treatment for this condition, but is associated with some disadvantages. Less invasive procedures and medical treatments are now available to treat these symptoms. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone acetate (Ryeqo^®; Myfembree^®) has been approved to treat symptoms of uterine fibroids. This combination works by suppressing ovarian hormone levels. In clinical trials, relugolix + estradiol/norethisterone substantially reduced menstrual bleeding and improved several other symptoms in women with uterine fibroids-associated heavy menstrual bleeding. The combination was generally well tolerated and had a minimal impact on bone loss, a known adverse effect of such therapies. With its convenient once-daily administration, relugolix/estradiol/norethisterone acetate is a useful addition to current medical treatment options for premenopausal women with symptomatic uterine fibroids.

Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.

BACKGROUND: Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids. METHODS: PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg linzagolix per day alone, (3) 100 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg linzagolix per day alone, or (5) 200 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed. FINDINGS: Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were excluded from the study, resulting in 501 women being included in the full analysis set. In both trials, a significantly higher proportion of women had a reduction in heavy menstrual bleeding in all linzagolix (with or without add-back therapy) treatment groups compared with the placebo group (p≤0·003). In PRIMROSE 1, the response rates were 56·4% (95% CI 45·8-66·6%) in the 100 mg group, 66·4% (56·6-75·2%) in the 100 mg plus add-back therapy group, 71·4% (61·8-79·8%) in the 200 mg group, and 75·5% (66·0-83·5%) in the 200 mg plus add-back therapy group, compared with 35·0% (25·8-45·0%) in the placebo group. In PRIMROSE 2, the response rates were 56·7% (46·3-66·7%) in the 100 mg group, 77·2% (67·8-85·0%) in the 100 mg plus add-back therapy group, 77·7% (68·4-85·3%) in the 200 mg group, and 93·9% (87·1-97·7%) in the 200 mg plus add-back therapy group, compared with 29·4% (20·8-39·3%) with placebo. The most common adverse events up to 24 weeks were hot flushes (35% of participants in PRIMROSE 1 and 32% in PRIMROSE 2 with linzagolix [200 mg] alone and 3-14% in all other groups). INTERPRETATION: Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly reduced heavy menstrual bleeding. Partial suppression with once-per-day linzagolix (100 mg) without add-back therapy potentially provides a unique option for the chronic treatment of symptomatic uterine fibroids in women who cannot or do not want to take concomitant hormonal add-back therapy. FUNDING: ObsEva.

Effects of ultra-low dose hormone therapy on biochemical bone turnover markers in postmenopausal women: A randomized, placebo-controlled, double-blind trial.

OBJECTIVE: Evaluate the effects of ultra-low-dose hormone therapy (Ultra-LD HT) with 17ß-estradiol 0.5 mg and norethisterone acetate 0.1 mg (E2 0.5/NETA 0.1) versus placebo on bone turnover markers (BTM) in postmenopausal women. STUDY DESIGN: A multicenter, double-blind, randomized, placebo-controlled study was performed with 107 participants who received one tablet daily of E2 0.5/NETA 0.1 or placebo for 24-weeks. Bone formation markers-N-terminal propeptide of type I procollagen (PINP) and Bone-specific alkaline phosphatase (BSAP), and bone resorption markers-C-telopeptide of type I collagen (CTX-I) and N-telopeptide crosslinked of type I collagen (NTX) were assessed before and at 12 and 24-weeks of treatment. RESULTS: Women treated with E2 0.5/NETA 0.1 had a significant reduction in the PINP marker from baseline (58.49 ± 21.12 µg/L) to week 12 (48.31 ± 20.99 µg/L) and week 24 (39.16 ± 16.50 µg/L). Placebo group, the PINP marker did not differ significantly. The analysis of the BSAP indicated a significant increase in the placebo group (13.8 ± 5.09 µg/L and 16.29 ± 4.3 µg/L, at baseline and week 24, respectively), whereas in the treatment group the values did not change. The analysis of the NTX marker showed a significant reduction only in the treatment group (43.21 ± 15.26 nM/mM and 33.89 ± 14.9 nM/mM, at baseline and week 24, respectively). CTX-I had a significant decrease in the treatment group from baseline (0.3 ± 0.16 ng/L) to week 12 (0.21 ± 0.14 ng/L) and week 24 (0.21 ± 0.12 ng/L). CONCLUSION: Women receiving E2 0.5/NETA 0.1 experienced reductions in bone resorption and formation markers, an expected effect during the anti-resorptive therapy, suggesting a protective bone effect with the Ultra-LD HT.

Association of Progestogens and Venous Thromboembolism Among Women of Reproductive Age.

OBJECTIVE: To evaluate associations between use of seven progestogens and incident acute venous thromboembolism (VTE) among women of reproductive age. METHODS: This nested matched case-control study identified women aged 15-49 years from January 1, 2010, through October 8, 2018, in the IBM MarketScan databases, a nationwide sample of private insurance claims in the United States. After exclusions, 21,405 women with incident acute VTE (case group), identified by diagnosis codes, were matched 1:5 by year of birth and index date through risk set sampling to 107,025 women without prior VTE (control group). From lowest to highest systemic dose based on a modified hierarchy, progestogens studied were levonorgestrel-releasing intrauterine device (LNG-IUD), oral norethindrone, etonogestrel implant, oral progesterone, oral medroxyprogesterone acetate, oral norethindrone acetate, and depot medroxyprogesterone acetate (DMPA). Conditional logistic regression models adjusted for 16 VTE risk factors were used to estimate odds ratios and 99% CIs for incident acute VTE associated with current progestogen use compared with nonuse. The primary analysis treated each progestogen as a binary exposure. Dose, which varied for oral formulations, and chronicity were explored separately. Significance was set at P <.01 to allow for multiple comparisons. RESULTS: Current use of higher-dose progestogens was significantly associated with increased odds of VTE compared with nonuse (oral norethindrone acetate: adjusted odds ratio [aOR] 3.00, 99% CI 1.96-4.59; DMPA: aOR 2.37, 99% CI 1.95-2.88; and oral medroxyprogesterone acetate: aOR 1.98, 99% CI 1.41-2.80). Current use of other progestogens was not significantly different from nonuse (LNG-IUD, etonogestrel implant, and oral progesterone) or had reduced odds of VTE (oral norethindrone). Sensitivity analyses that assessed misclassification bias supported the primary findings. CONCLUSION: Among reproductive-aged women using one of seven progestogens, only use of norethindrone acetate and medroxyprogesterone acetate-considered higher-dose progestogens-was significantly associated with increased odds of incident acute VTE. The roles of progestogen type, dose, and indication for use warrant further study.