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Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids.
Schlaff, WD, Ackerman, RT, Al-Hendy, A, Archer, DF, Barnhart, KT, Bradley, LD, Carr, BR, Feinberg, EC, Hurtado, SM, Kim, J, et al
The New England journal of medicine. 2020;(4):328-340
Abstract
BACKGROUND Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. METHODS We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. RESULTS A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. CONCLUSIONS Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).
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A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging.
Jager, A, de Vries, EGE, der Houven van Oordt, CWM, Neven, P, Venema, CM, Glaudemans, AWJM, Wang, Y, Bagley, RG, Conlan, MG, Aftimos, P
Breast cancer research : BCR. 2020;(1):97
Abstract
BACKGROUND Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17β-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). METHODS Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ≥ 6 months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. RESULTS Patients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. CONCLUSION Elacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. TRIAL REGISTRATION ClinicalTrials.gov, NCT02650817 . Registered on 08 January 2016.
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Elagolix Alone or With Add-Back Therapy in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas: A Randomized Controlled Trial.
Carr, BR, Stewart, EA, Archer, DF, Al-Hendy, A, Bradley, L, Watts, NB, Diamond, MP, Gao, J, Owens, CD, Chwalisz, K, et al
Obstetrics and gynecology. 2018;(5):1252-1264
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Abstract
OBJECTIVE To evaluate elagolix, an oral gonadotropin-releasing hormone receptor antagonist, alone or with add-back therapy, in premenopausal women with heavy menstrual bleeding (greater than 80 mL per month) associated with uterine leiomyomas. METHODS This double-blind, randomized, placebo-controlled, parallel-group study evaluated efficacy and safety of elagolix in cohorts 1 (300 mg twice daily) and 2 (600 mg daily) with four arms per cohort: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.1 norethindrone acetate, and elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate. A sample size of 65 per group was planned to compare elagolix with add-back to placebo on the primary end point: the percentage of women who had less than 80 mL menstrual blood loss and 50% or greater reduction in menstrual blood loss from baseline to the last 28 days of treatment. Safety assessments included changes in bone mineral density. RESULTS From April 8, 2013, to December 8, 2015, 571 women were enrolled, 567 were randomized and treated (cohort 1=259; cohort 2=308), and 80% and 75% completed treatment, respectively. Participants had a mean±SD age of 43±5 years (cohort 2, 42±5 years), and 70% were black (cohort 2, 74%). Primary end point responder rates in cohort 1 (cohort 2) were 92% (90%) for elagolix alone, 85% (73%) for elagolix with 0.5 mg estradiol/0.1 mg norethindrone acetate, 79% (82%) for elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate, and 27% (32%) for placebo (all P<.001 vs placebo). Elagolix groups had significant decreases compared with placebo in lumbar spine bone mineral density, which was attenuated by adding 1.0 mg estradiol/0.5 mg norethindrone acetate. CONCLUSION Elagolix with and without add-back significantly reduced menstrual blood loss in women with uterine leiomyomas. Add-back therapy reduced hypoestrogenic effects on bone mineral density. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT01817530; EU Clinical Trial Register, 2013-000082-37.
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Pharmacokinetic interaction between the CYP3A4 inhibitor ketoconazole and the hormone drospirenone in combination with ethinylestradiol or estradiol.
Wiesinger, H, Berse, M, Klein, S, Gschwend, S, Höchel, J, Zollmann, FS, Schütt, B
British journal of clinical pharmacology. 2015;(6):1399-410
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Abstract
AIMS: The present study was conducted to investigate the influence of the strong CYP3A4 inhibitor ketoconazole (KTZ) on the pharmacokinetics of drospirenone (DRSP) administered in combination with ethinylestradiol (EE) or estradiol (E2). METHODS This was a randomized, multicentre, open label, one way crossover, fixed sequence study with two parallel treatment arms. A group sequential design allowed terminating the study for futility after first study cohort. About 50 healthy young women were randomized 1 : 1 to 'DRSP/EE' or 'DRSP/E2'. Subjects in the 'DRSP/EE' group received DRSP 3 mg/EE 0.02 mg (YAZ®, Bayer) once daily for 21 to 28 days followed by DRSP 3 mg/EE 0.02 mg once daily plus KTZ 200 mg twice daily for 10 days. Subjects in the 'DRSP/E2' group received DRSP 3 mg/E2 1.5 mg (research combination) once daily for 21 to 28 days followed by DRSP 3 mg/E2 1.5 mg once daily plus KTZ 200 mg twice daily for 10 days. RESULTS Oral co-administration of DRSP/EE or DRSP/E2 and KTZ resulted in an increase in DRSP exposure (AUC(0,24 h)) in both treatment groups: DRSP/EE group: 2.68-fold DRSP increase (90% CI 2.44, 2.95); DRSP/E2 group: 2.30-fold DRSP increase (90% CI 2.08, 2.54). EE and estrone (metabolite of E2) exposures were increased ~1.4-fold whereas E2 exposure was largely unaffected by KTZ co-administration. CONCLUSIONS A moderate pharmacokinetic drug-drug interaction between DRSP and KTZ was demonstrated in this study. No relevant changes of medical concern were detected in the safety data collected in this study.
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Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism.
Ågren, UM, Anttila, M, Mäenpää-Liukko, K, Rantala, ML, Rautiainen, H, Sommer, WF, Mommers, E
The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception. 2011;(6):444-57
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OBJECTIVES To compare the effects of a combined oral contraceptive (COC) containing nomegestrol acetate and 17β-oestradiol (NOMAC/E2) on haemostasis, lipids, carbohydrate metabolism, C-reactive protein (CRP) and sex hormone-binding globulin (SHBG) with those of a COC containing levonorgestrel and ethinylestradiol (LNG/EE). METHODS In a randomised, open-label study, 121 healthy women, 18-50 years of age, were randomly assigned to receive NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n=60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n=61) for six cycles. The primary outcome was the change from baseline to cycle 6 for all indices. RESULTS All parameters were similar at baseline between the two groups. Over six cycles, NOMAC/E2 had less effect on most haemostatic indices than LNG/EE. Lipids were essentially unchanged with NOMAC/E2, whereas with LNG/EE high-density lipoprotein cholesterol decreased and low-density lipoprotein cholesterol and triglycerides slightly increased. NOMAC/E2 induced negligible changes in glucose and insulin parameters, in contrast to LNG/EE. A much smaller increase in CRP was observed with NOMAC/E2 than with LNG/EE. NOMAC/E2 was associated with a greater increase in SHBG. CONCLUSIONS The monophasic COC NOMAC/E2 had less influence on haemostasis, lipids and carbohydrate metabolism than the COC LNG/EE.
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Cardiovascular risk markers during treatment with estradiol and trimegestone or dydrogesterone.
Hellgren, M, Conard, J, Norris, L, Kluft, C
Maturitas. 2009;(3):287-93
Abstract
OBJECTIVE To study cardiovascular risk markers in women taking estradiol/trimegestone or estradiol/dydrogesterone. DESIGN Multicenter, randomized, prospective, double-blind study of 184 healthy post-menopausal women randomized to 6 cycles of either estradiol (2mg)+trimegestone (0.5mg) (T-group) or estradiol (2mg)+dydrogesterone (10mg) (DYDR group). Cardiovascular risk markers were measured before, after cycle 1, 3 and 6 and at 4 weeks post-treatment. RESULTS Fibrinogen was reduced in both groups but more markedly in the DYDR group. Factor VIIc activity levels decreased in both groups with a greater change in the T-group. Factor VII antigen was increased in both groups with a greater increase in the DYDR group. Factor VIIa was increased in the DYDR group only. Plasminogen levels were also increased in both groups with a greater increase in the T-group. There were no statistically significant changes in lipid variables between the different regimens. Changes in total cholesterol and LDL cholesterol were correlated positively with changes in factor VIIc in the DYDR group and negatively with changes in factor VIIc in the T-group. Trigemestone was associated with a better bleeding pattern. CONCLUSIONS Trimegestone was associated with less procoagulant changes in factor VIIa and factor VIIc activity and larger decrease in PAI-1 activity compared with the dydrogesterone preparation. These results reflect less androgenic properties of the trimegestone preparation. The fibrinogen level and Lp(a) were more decreased during dydrogesterone treatment. Further investigation is required to clarify the relative importance of beneficial effects with respect to cardiovascular risk.
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Effects of E2 and E2/norgestimate hormone therapy on elevated baseline lipids.
Langer, RD, Friedman, AJ
The Journal of reproductive medicine. 2006;(8):610-6
Abstract
OBJECTIVE To evaluate lipid effects of estradiol/ norgestimate hormone therapy in postmenopausal women with elevated lipid levels. STUDY DESIGN Postmenopausal women were randomized to E2, 1 mg/intermittent norgestimate (NGM) 90 microg (n = 31), or opposed E2, 1 mg (n = 36), in a 12-month trial. A subset analysis was conducted on participants with unfavorable baseline lipid levels, either total cholesterol (TC) levels > 200 mg/dL, high-density lipoprotein cholesterol (HDL-C) levels < 40 mg/dL, low-density lipoprotein cholesterol (LDL-C) levels > or = 160 mg/dL or triglyceride levels > or = 150 mg/dL. Mean changes and categorical shifts were assessed on fasting blood samples collected at baseline and at 7 and 12 months. RESULTS Twelve-month mean changes from baseline in women treated with E2/NGM included a 19.8% increase in HDL-C and decreases of 13.4% in LDL-C, 17.5% in triglycerides and 3.3% in TC. Women with poorer lipid profiles at baseline showed the greatest benefit. Results were similar in women randomized to unopposed E2. CONCLUSION E2/NGM and unopposed E2 were similarly beneficial in modifying lipid fractions in women with unfavorable baseline levels.
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Intranasal continuous combined 17 beta-estradiol/norethisterone therapy improves the lipid profile in healthy postmenopausal women.
Hemelaar, M, Kenemans, P, de Bie, L, van de Weijer, PH, van der Mooren, MJ
Fertility and sterility. 2006;(4):979-88
Abstract
OBJECTIVE To compare the effects of continuous combined 17beta-estradiol (E2) plus norethisterone (acetate) [NET(A)] therapy by either intranasal or oral administration on the lipid profile in postmenopausal women. DESIGN Randomized, double-blind, multicenter trial. SETTING Gynecologic outpatient department. PATIENT(S): Two-hundred thirty-three healthy postmenopausal women. INTERVENTION(S): Women received continuous combined hormone therapy, either intranasal E2/NET (175 microg/275 microg) as a spray (n = 117) or oral E2/NETA (1 mg/0.5 mg) as a capsule (n = 116), for 1 year. MAIN OUTCOME MEASURE(S): Fasting plasma concentrations of lipids and (apo)lipoproteins; and atherogenic indices at baseline and after 12, 24, and 52 weeks of treatment. RESULT(S): We found a significant (P < .001) decrease from baseline in both treatment groups in total, low-density lipoprotein- (LDL), high-density lipoprotein- (HDL), and HDL2-cholesterol, in triglycerides, apolipoprotein B (apoB), and lipoprotein(a). Levels of HDL3-cholesterol and apolipoprotein A1 (apoA1) were transiently decreased in the intranasal group. In the oral group, compared with the intranasal group, the decrease was larger for ratio total and LDL-cholesterol and lipoprotein(a) and smaller for triglycerides and apoA1. In the oral group, the ratios total/HDL cholesterol and LDL/HDL cholesterol were lowered, and the ratio apoB/LDL was increased, more than in the intranasal group. CONCLUSION(S): Both intranasal and oral E2/NET(A) therapy improved the lipid profile of healthy postmenopausal women, with some effects being more pronounced after oral administration.
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Antihypertensive effects of drospirenone with 17beta-estradiol, a novel hormone treatment in postmenopausal women with stage 1 hypertension.
White, WB, Pitt, B, Preston, RA, Hanes, V
Circulation. 2005;(13):1979-84
Abstract
BACKGROUND Drospirenone (DRSP) is a novel progestin with antimineralocorticoid activity that has been developed for hormone therapy in combination with 17beta-estradiol (E2) in postmenopausal women. In prior studies with DRSP in postmenopausal women that were focused on relief of menopausal symptoms, DRSP/E2 yielded significant reductions in blood pressure (BP). METHODS AND RESULTS The effects of 3 mg DRSP/1 mg E2 on clinic and 24-hour ambulatory BP as well as potassium homeostasis were evaluated in postmenopausal women with stage 1 hypertension (systolic, 140 to 159 and/or diastolic, 90 to 99 mm Hg) in a 12-week, multicenter, double-blind, randomized, placebo-controlled study. Clinic BPs were measured at baseline and at 2, 4, 6, 8, and 12 weeks of therapy, whereas potassium was measured at 2, 6, and 12 weeks of therapy. Ambulatory BP was performed in a substudy at baseline and at the end of the trial. In the intention-to-treat population of 213 women, the clinic BP was reduced significantly on DRSP/E2 (clinic BP, -14.1/-7.9 for DRSP/E2 versus -7.1/-4.3 mm Hg for placebo, P<0.0001). In the subgroup of 43 women with ambulatory BP monitoring, the 24-hour BP fell by -8.5/-4.2 mm Hg versus -1.8/-1.6 mm Hg on placebo (P=0.002/0.07). There were no significant changes from baseline in potassium levels or in the incidence of hyperkalemia (> or =5.5 meq/L) on DRSP/E2 compared with placebo. CONCLUSIONS Combination therapy with DRSP/E2 significantly lowered both clinic and 24-hour systolic BP in postmenopausal women with stage 1 systolic hypertension. This characteristic may lead to benefit for cardiovascular risk reduction in this population.
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Oral, more than transdermal, estrogen therapy improves lipids and lipoprotein(a) in postmenopausal women: a randomized, placebo-controlled study.
Hemelaar, M, van der Mooren, MJ, Mijatovic, V, Bouman, AA, Schijf, CP, Kroeks, MV, Franke, HR, Kenemans, P
Menopause (New York, N.Y.). 2003;(6):550-8
Abstract
OBJECTIVE To assess the effects of low-dose oral and transdermal estrogen therapy on the lipid profile and lipoprotein(a) [Lp(a)] levels in healthy, postmenopausal women and to study the additional influence of gestodene administration. DESIGN In a multicenter, randomized, double-blind, placebo-controlled study, 152 healthy, hysterectomized, postmenopausal women received daily either placebo (n = 49), 50 microg transdermal 17beta-estradiol (tE2, n = 33), 1 mg oral 17beta-estradiol (oE2, n = 37), or 1 mg oE2 combined with 25 microg gestodene (oE2 + G, n = 33) for 13 cycles of 28 days, followed by 4 cycles of placebo in each group. Fasting serum concentrations of total, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp(a) were measured at baseline and in cycles 4, 13, and 17. RESULTS In cycle 13, a significant mean percentage decrease from baseline was found in all treatment groups compared with placebo in total cholesterol (tE2, -4.7%; oE2, -6.9%; oE2 + G, -10.5%) and LDL cholesterol (tE2, -5.8%; oE2, -12.6%; oE2 + G, -13.6%). For both oral groups, the reductions were already significant in cycle 4. None of the treatment groups showed a significant change in HDL cholesterol or triglycerides. In cycle 13, Lp(a) was decreased compared with placebo in the oE2 group (-6.6%) and the oE2 + G group (-8.2%). After washout, all observed changes had returned to baseline level, except for the decreases in total and LDL cholesterol in the oE2 + G group. CONCLUSIONS Oral E2 and E2 + G, and to a lesser extent transdermal E2, decreased total and LDL cholesterol. Lp(a) was lowered only by the oral treatments.