-
1.
Does preoperative locally applied estrogen treatment facilitate prolapse-associated symptoms in postmenopausal women with symptomatic pelvic organ prolapse? A randomised controlled double-masked, placebo-controlled, multicentre study.
Marschalek, ML, Bodner, K, Kimberger, O, Zehetmayer, S, Morgenbesser, R, Dietrich, W, Obruca, C, Husslein, H, Umek, W, Koelbl, H, et al
BJOG : an international journal of obstetrics and gynaecology. 2021;(13):2200-2208
-
-
Free full text
-
Abstract
OBJECTIVE To evaluate whether locally applied vaginal estrogen affects prolapse-associated complaints compared with placebo treatment in postmenopausal women prior to surgical prolapse repair. DESIGN Randomised, double-masked, placebo-controlled, multicentre study. SETTING Urogynaecology unit at the Medical University of Vienna and University Hospital of Tulln. POPULATION Postmenopausal women with symptomatic pelvic organ prolapse and planned surgical prolapse repair. METHODS Women were randomly assigned local estrogen cream or placebo cream 6 weeks preoperatively. MAIN OUTCOME MEASURES The primary outcome was differences in subjective prolapse-associated complaints after 6 weeks of treatment prior to surgery, assessed with the comprehensive German pelvic floor questionnaire. Secondary outcomes included differences in other pelvic floor-associated complaints (bladder, bowel or sexual function). RESULTS Out of 120 women randomised, 103 (86%) remained for the final analysis. After 6 weeks of treatment the prolapse domain score did not differ between the estrogen and the placebo groups (4.4 ± 0.19 versus 4.6 ± 0.19; mean difference, -0.21; 95% CI -0.74 to 0.33; P = 0.445). Multivariate analysis, including only women receiving the intervention, showed that none of the confounding factors modified the response to estradiol. CONCLUSIONS These results demonstrate that preoperative locally applied estrogen does not ameliorate prolapse-associated symptoms in postmenopausal women with symptomatic pelvic organ prolapse. TWEETABLE ABSTRACT Preoperative local estrogen does not ameliorate prolapse-associated symptoms in postmenopausal women with pelvic organ prolapse.
-
2.
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.).
-
3.
The Use of Transdermal Estrogen in Castrate-resistant, Steroid-refractory Prostate Cancer.
Smith, K, Galazi, M, Openshaw, MR, Wilson, P, Sarker, SJ, O'Brien, N, Alifrangis, C, Stebbing, J, Shamash, J
Clinical genitourinary cancer. 2020;(3):e217-e223
Abstract
BACKGROUND Androgen-deprivation therapy is the mainstay of treatment for metastatic prostate cancer. Corticosteroids and estrogens are also useful agents in castration-resistant prostate cancer (CRPC). However, oral estrogens are associated with thromboembolic events, which limits their use, and transdermal estrogens may offer a safer alternative. This study was carried out to determine the safety and effectiveness of transdermal estrogens in CRPC. PATIENTS AND METHODS Forty-one patients with CRPC and steroid-resistant prostate cancer were eligible for this dose-escalation study of transdermal estradiol. A starting dose of 50 mcg/24 hours was applied and increased if prostate-specific antigen (PSA) rose > 5 ng/mL in steps to 300 mcg/24 hours. The primary endpoint was PSA response, and secondary outcomes included incidence of thromboembolic events and progression-free survival. Patients who progressed were offered diethylstilbestrol. RESULTS Five (13%) of 40 patients had > 50% PSA reduction for at least 1 month at any transdermal estradiol dose. No venous-thromboembolic events were observed, and responses plateaued at 200 mcg/24 hours. A correlation between PSA response and rising sex hormone binding globulin was seen. Fifty percent of patients subsequently responded to low-dose diethylstilbestrol. CONCLUSION Transdermal estradiol appears to be a low toxicity treatment option to control CRPC after failure of steroid therapy. Modulation of sex hormone binding globulin by transdermal estradiol may be one mechanism of action of estrogens on CRPC. Oral estrogens remain effective after the use of transdermal estradiol.
-
4.
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
-
-
Free full text
-
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.
-
5.
Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
Friedenreich, CM, Neilson, HK, Wang, Q, Stanczyk, FZ, Yasui, Y, Duha, A, MacLaughlin, S, Kallal, C, Forbes, CC, Courneya, KS
Endocrine-related cancer. 2015;(5):863-76
Abstract
Exercise dose comparison trials with biomarker outcomes can identify the amount of exercise required to reduce breast cancer risk and also strengthen the causal inference between physical activity and breast cancer. The Breast Cancer and Exercise Trial in Alberta (BETA) tested whether or not greater changes in estradiol (E2), estrone, and sex hormone-binding globulin (SHBG) concentrations can be achieved in postmenopausal women randomized to 12 months of HIGH (300 min/week) vs MODERATE (150 min/week) volumes of aerobic exercise. BETA included 400 inactive postmenopausal women aged 50-74 years with BMI of 22-40 kg/m(2). Blood was drawn at baseline and 6 and 12 months. Adiposity, physical fitness, diet, and total physical activity were assessed at baseline and 12 months. Intention-to-treat analyses were performed using linear mixed models. At full prescription, women exercised more in the HIGH vs MODERATE group (median min/week (quartiles 1,3): 253 (157 289) vs 137 (111 150); P<0.0001). Twelve-month changes in estrogens and SHBG were <10% on average for both groups. No group differences were found for E2, estrone, SHBG or free E2 changes (treatment effect ratios (95% CI) from linear mixed models: 1.00 (0.96-1.06), 1.02 (0.98-1.05), 0.99 (0.96-1.02), 1.01 (0.95, 1.06), respectively, representing the HIGHMODERATE ratio of geometric mean biomarker levels over 12 months; n=382). In per-protocol analyses, borderline significantly greater decreases in total and free E2 occurred in the HIGH group. Overall, no dose effect was observed for women randomized to 300 vs 150 min/week of moderate to vigorous intensity exercise who actually performed a median of 253 vs 137 min/week. For total and free E2, the lack of differential effect may be due to modest adherence in the higher dose group.
-
6.
Association between vitamin D concentration and levels of sex hormones in an elderly Polish population with different genotypes of VDR polymorphisms (rs10735810, rs1544410, rs7975232, rs731236).
Laczmanski, L, Lwow, F, Mossakowska, M, Puzianowska-Kuznicka, M, Szwed, M, Kolackov, K, Krzyzanowska-Swiniarska, B, Bar-Andziak, E, Chudek, J, Sloka, N, et al
Gene. 2015;(1):73-6
Abstract
BACKGROUND Vitamin D co-regulates the synthesis of sex hormones in part by interaction with its nuclear receptor. The aim of this study was to determine whether there is an association of vitamin D concentration vs the level of sex hormones in elderly Polish individuals with different genotypes of the vitamin D receptor (VDR) gene. MATERIALS AND METHODS Rs10735810, rs1544410, rs7975232, and rs731236 polymorphisms of VDR, the serum sex hormone level, free estrogen index (FEI) and free androgen index (FAI) as well as vitamin D, were evaluated in 766 persons (362 women and 404 men) selected from 5695 Polish population, aged 65-90years from the PolSenior survey. RESULTS We observed that women with GG (rs731236), TT (rs7975232), BB (rs1544410) and FF (rs10735810) genotypes were characterized by a significant correlation between vitamin D vs testosterone concentration and FAI value. We found a significant correlation between testosterone level and FAI vs vitamin D concentration in men with heterozygote AG in the rs731236 polymorphism and in the GG (rs7975232), the BB (rs1544410), and the Ff (rs10735810) genotypes. CONCLUSION In elderly selected Polish population with different genotypes of VDR polymorphisms, a statistically significant relationship between vitamin D concentration vs testosterone level was observed.
-
7.
Discordant association of C-reactive protein with clinical events and coronary luminal narrowing in postmenopausal women: data from the Women's Angiographic Vitamin and Estrogen (WAVE) study.
Patel, D, Jhamnani, S, Ahmad, S, Silverman, A, Lindsay, J
Clinical cardiology. 2013;(9):535-41
Abstract
BACKGROUND The incidence of cardiovascular events had been shown to be associated with C-reactive protein (CRP). However, it is unclear that the cardiovascular risk associated with CRP is due to progressive coronary narrowing or to other factors such as formation of unstable plaque. This study was designed to determine the effect of baseline CRP on cardiovascular events and on the progression of atherosclerotic narrowing among 423 postmenopausal women with angiographic stenosis between 15% and 75%. HYPOTHESIS Baseline CRP levels may affect cardiovascular events and progression of atherosclerotic coronary artery narrowing among postmenopausal women. METHODS Baseline and follow-up (2.8 years) angiographic data were analyzed among 320 women. Women were stratified into 4 quartiles according to baseline CRP levels. The changes in lumen diameter and clinical events in each quartile were compared. RESULTS The annualized changes in minimal and average lumen diameter in diseased and nondiseased coronary segments were not significantly associated with baseline CRP levels. The composite end point of all-cause mortality and myocardial infarction (MI) increased from 3% (3/107) in the first CRP quartile to 14% (14/98) in fourth CRP quartile (P < 0.001). Similar results were found for cardiovascular death and MI (increased from 1% (2/107) in the first quartile to 11% (11/98) in fourth quartile). The difference remained significant even after adjustment for baseline differences and cardiovascular risk factors. CONCLUSIONS Higher baseline CRP was associated with increased risk of clinical events but was not associated with annualized change in luminal diameters. Thus, increased risk of adverse events among patients with higher baseline CRP events was independent of progression of atherosclerosis as measured by change in minimal or average luminal diameter.
-
8.
Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09).
Langley, RE, Cafferty, FH, Alhasso, AA, Rosen, SD, Sundaram, SK, Freeman, SC, Pollock, P, Jinks, RC, Godsland, IF, Kockelbergh, R, et al
The Lancet. Oncology. 2013;(4):306-16
Abstract
BACKGROUND Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. METHODS In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 μg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784. FINDINGS 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12-31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7-14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0-15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and -0·16 mmol/L (-2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and -0·23 mmol/L (-3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 [19%] of 78 patients in the LHRHa group vs 104 [75%] of 138 in the oestrogen-patch group), hot flushes (44 [56%] vs 35 [25%]), and dermatological problems (10 [13%] vs 58 [42%]). INTERPRETATION Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival. FUNDING Cancer Research UK, MRC Clinical Trials Unit.
-
9.
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.
-
10.
Key lipogenic gene expression can be decreased by estrogen in human adipose tissue.
Lundholm, L, Zang, H, Hirschberg, AL, Gustafsson, JA, Arner, P, Dahlman-Wright, K
Fertility and sterility. 2008;(1):44-8
Abstract
OBJECTIVE To characterize the molecular mechanisms by which estrogens reduce adipose tissue mass, with particular focus on genes involved in lipogenesis. DESIGN This study involves one arm of an open randomized clinical study with parallel group comparison. SETTING Women's health clinical research unit at a university hospital and a university research laboratory. PATIENT(S): Samples from ten naturally postmenopausal women are included in the study. INTERVENTION(S): The participants were studied before and after 3 months of treatment with estradiol valerate (2 mg daily). MAIN OUTCOME MEASURE(S): Affymetrix gene chips were used to study changes in gene expression upon estrogen treatment in subcutaneous abdominal adipose tissue. RESULT(S): Genes involved in fatty acid synthesis, such as stearoyl-CoA desaturase, fatty acid synthase, acetyl-coenzyme A carboxylase alpha, and fatty acid desaturase 1 were decreased by estrogen treatment in a subgroup of women. Changes in the expression of these genes were correlated to changes in plasma triglyceride levels. Another gene decreased by estrogen treatment was peroxisome proliferator activated receptor gamma (PPARG). CONCLUSION(S): Key lipogenic genes and the important adipogenic gene PPARG can be regulated by estrogen in human abdominal adipose tissue, which could be relevant for increased adiposity following menopause.