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Effect of Transdermal Estradiol and Insulin-like Growth Factor-1 on Bone Endpoints of Young Women With Anorexia Nervosa.
Singhal, V, Bose, A, Slattery, M, Haines, MS, Goldstein, MA, Gupta, N, Brigham, KS, Ebrahimi, S, Javaras, KN, Bouxsein, ML, et al
The Journal of clinical endocrinology and metabolism. 2021;(7):2021-2035
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CONTEXT Anorexia nervosa (AN) is prevalent in adolescent girls and is associated with bone impairment driven by hormonal alterations in nutritional deficiency. OBJECTIVE To assess the impact of estrogen replacement with and without recombinant human insulin-like growth factor-1 (rhIGF-1) administration on bone outcomes. DESIGN Double-blind, randomized, placebo-controlled 12-month longitudinal study. PARTICIPANTS Seventy-five adolescent and young adult women with AN age 14 to 22 years. Thirty-three participants completed the study. INTERVENTION Transdermal 17-beta estradiol 0.1 mg/day with (i) 30 mcg/kg/dose of rhIGF-1 administered subcutaneously twice daily (AN-IGF-1+) or (ii) placebo (AN-IGF-1-). The dose of rhIGF-1 was adjusted to maintain levels in the upper half of the normal pubertal range. MAIN OUTCOME MEASURES Bone turnover markers and bone density, geometry, microarchitecture, and strength estimates. RESULTS Over 12 months, lumbar areal bone mineral density increased in AN-IGF-1- compared to AN-IGF-1+ (P = 0.004). AN-IGF-1+ demonstrated no improvement in areal BMD in the setting of variable compliance to estrogen treatment. Groups did not differ for 12-month changes in bone geometry, microarchitecture, volumetric bone mineral density (vBMD), or strength (and results did not change after controlling for weight changes over 12 months). Both groups had increases in radial cortical area and vBMD, and tibia cortical vBMD over 12 months. Levels of a bone resorption marker decreased in AN-IGF-1- (P = 0.042), while parathyroid hormone increased in AN-IGF-1+ (P = 0.019). AN-IGF-1- experienced irregular menses more frequently than did AN-IGF-1+, but incidence of all other adverse events did not differ between groups. CONCLUSIONS We found no additive benefit of rhIGF-1 administration for 12 months over transdermal estrogen replacement alone in this cohort of young women with AN.
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Lessons from KEEPS: the Kronos Early Estrogen Prevention Study.
Miller, VM, Taylor, HS, Naftolin, F, Manson, JE, Gleason, CE, Brinton, EA, Kling, JM, Cedars, MI, Dowling, NM, Kantarci, K, et al
Climacteric : the journal of the International Menopause Society. 2021;(2):139-145
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The Kronos Early Estrogen Prevention Study (KEEPS) was a randomized, double-blind, placebo-controlled trial designed to determine the effects of hormone treatments (menopausal hormone treatments [MHTs]) on the progression of carotid intima-medial thickness (CIMT) in recently menopausal women. Participants less than 3 years from menopause and without a history of overt cardiovascular disease (CVD), defined as no clinical CVD events and coronary artery calcium < 50 Agatston units, received either oral conjugated equine estrogens (0.45 mg/day) or transdermal 17β-estradiol (50 µg/day), both with progesterone (200 mg/day for 12 days/month), or placebo pills and patches for 4 years. Although MHT did not decrease the age-related increase in CIMT, KEEPS provided other important insights about MHT effects. Both MHTs versus placebo reduced the severity of menopausal symptoms and maintained bone density, but differed in efficacy regarding mood/anxiety, sleep, sexual function, and deposition of β-amyloid in the brain. Additionally, genetic variants in enzymes for metabolism and uptake of estrogen affected the efficacy of MHT for some aspects of symptom relief. KEEPS provides important information for use of MHT in clinical practice, including type, dose, and mode of delivery of MHT recently after menopause, and how genetic variants in hormone metabolism may affect MHT efficacy on specific outcomes.
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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
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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.
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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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Bone protection for early menopausal women in China: standard or half-dose estrogen with progestin? A one-year prospective randomized trail.
Zhu, SY, Deng, Y, Wang, YF, Xue, W, Ma, X, Sun, A
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2019;(2):165-169
Abstract
The aim of the study is to compare the bone sparing effect of half-dose with standard-dose conjugated equine estrogen (CEE) combined with progestin. A total of 123 participants were administrated with 0.625 mg of CEE and 100 mg of micronized progesterone (MP) in group A, 0.3 mg of CEE and 100 mg of MP in group B, 0.625 mg of CEE and 10 mg of dydrogesterone (DDG) in group C for one year. Percent changes from baseline in BMD at lumbar spine and fracture rate were primary outcomes. Secondary endpoints included changes of BMD at femoral neck, total hip and arm, bone markers (alkaline phosphatase, calcium and phosphorus), serum alanine aminotransferase (ALT) and endometrial thickness. No fractures occurred during the treatment. Standard dose of CEE leads to significant changes in lumbar spine and arm. The 3.78% growth of BMD at femoral neck in group C marked a statistically difference. There was no statistically remarkable bone loss at hip in all three groups. Bone turnover markers and ALT significantly decreased from basic values. Endometrium thickened more with traditional dose of CEE. Both the half and standard dose CEE are effective in BMD preservation among early menopausal women with subtle side effects. Low-dose estrogen is less efficacious than traditional one.
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Comparison Of Cimicifuga foetida extract and different hormone therapies regarding in causing breast pain in early postmenopausal women.
Wang, YP, Ma, D, Cheng, XT, Zhang, SJ, Xue, W, Deng, Y, Wang, YF, Sun, AJ
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2019;(2):160-164
Abstract
This study aimed to compare the influence between Cimicifuga foetida extract and different hormone therapies on breast pain in early postmenopausal women. A prospective, randomized, controlled clinical trial was conducted among 96 early postmenopausal women. Participants were randomly assigned to three groups: group A received 1 mg/day estradiol valerate plus 4 mg/day medroxyprogesterone acetate on days 19-30; group B received 1 mg/day estradiol valerate plus 100 mg/day micronized progesterone on days 19-30; group C received C. foetida extract, 1talet (contains 33.3 mg extract), t.i.d. Breast pain diary and numerical rating scale was used to access the breast pain. For 6 months' treatment, the total incidence of breast pain in group A and B was significantly higher than that in group C (p < .05). The duration (day) of breast pain in each month decreased over time in group A and B while it was continuously low and without significant change in group C (p > .05). The intensity of breast pain was mild in most participants and did not differ among three groups (p > .05). During treatment of early postmenopausal women with C. foetida extract for 6 months, the incidence and duration of breast pain were lower than upon treatment with E2 plus cyclic MPA or m-P and did not change over time.
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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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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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A Double-Blind Randomized Pilot Study Evaluating the Safety and Efficacy of Topical MEP in the Facial Appearance Improvement of Estrogen Deficient Females.
Draelos, ZD
Journal of drugs in dermatology : JDD. 2018;(11):1186 - 1189
Abstract
Facial skin aging is accelerated in postmenopausal females due to decreased collagen, reduced hydration, and loss of skin elasticity constituting the characteristics of estrogen deficient skin (EDS). The presence of estrogen receptors on dermal fibroblasts and epidermal keratinocytes confirms the role of estrogen in skin health. This research examined the efficacy and tolerability of topical methyl estradiolpropanoate (MEP) as an anti-aging cosmeceutical with estrogen like cutaneous effects in postmenopausal women who had never taken hormone replacement therapy (HRT). MEP was applied to the face twice daily for 14 weeks but was metabolized in the skin to an inactive compound avoiding estrogen side effects, as demonstrated by the safety study. The efficacy study investigator noted MEP induced statistically significant improvement from baseline at week 14 in dryness (P<0.001), laxity (P=0.001), atrophy (P=0.003), and dullness (P<0.001) as compared to vehicle. Four of nine subjects in the biopsy sub study demonstrated an increase in fibroblasts estrogen receptor staining. The novel concept of a safe and efficacious soft estrogen facial cosmeceutical may provide appearance benefits for postmenopausal women.
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Comparison of Pueraria mirifica gel and conjugated equine estrogen cream effects on vaginal health in postmenopausal women.
Suwanvesh, N, Manonai, J, Sophonsritsuk, A, Cherdshewasart, W
Menopause (New York, N.Y.). 2017;(2):210-215
Abstract
OBJECTIVES To compare the effects of a 12-week treatment with Pueraria mirifica (PM) gel or a conjugated estrogen cream on vaginal maturation index, vaginal symptom score, vaginal health assessment score, and vaginal flora in postmenopausal women. METHODS In a prospective, noninferiority, randomized controlled study, 82 postmenopausal women with at least one vulvovaginal symptom, that is, dryness, soreness, irritation, dyspareunia, or discharge, were recruited. Participants were randomly assigned into two groups for treatment with either PM gel or conjugated estrogen cream (CEE). The treatment regimen consisted of application of 0.5 g of product intravaginally daily for 2 weeks, and then decreased to three times per week for 10 weeks. Vaginal maturation index, vaginal symptoms score, and vaginal health assessment score were evaluated before the beginning of the study and at 6 weeks and 12 weeks after treatment with PM or CEE. RESULTS The vaginal maturation index increased significantly in both treatment groups at week 12, from 22.44 ± 22.28 to 47.56 ± 29.00 and from 27.07 ± 26.12 to 66.90 ± 22.42 in the PM and the CEE groups, respectively (P < 0.05). A significantly higher effect was, however, observed in the CEE group (P < 0.05). Vaginal symptom scores decreased significantly after treatment in both groups, from 4.37 ± 2.79 to 0.95 ± 1.88 and from 4.15 ± 2.16 to 0.68 ± 1.64 in the PM and the CEE groups, respectively (P < 0.05), with no statistically significant different between the two groups (P > 0.05). CONCLUSIONS The use of a 12-week treatment regimen with Pueraria mirifica gel was shown to be efficacious and safe for the treatment of vulvovaginal atrophy. Conjugated estrogen cream was found to be more effective compared to Pueraria mirifica gel in improving signs of vaginal atrophy and restoring vaginal epithelium at 6 and 12 weeks.
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Hepatic Effects of Estrogen on Plasma Distribution of Small Dense Low-Density Lipoprotein and Free Radical Production in Postmenopausal Women.
Nii, S, Shinohara, K, Matsushita, H, Noguchi, Y, Watanabe, K, Wakatsuki, A
Journal of atherosclerosis and thrombosis. 2016;(7):810-8
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AIM: Hepatic effects of estrogen therapy on low-density lipoprotein (LDL) subfraction or oxidative stress have not been previously evaluated. The purpose of the present study was to investigate whether the differential hepatic effects of estrogen affect plasma distribution of small dense LDL and free radical production in postmenopausal women. METHODS In all, 45 postmenopausal women were given 0.625 mg/day of oral conjugated equine estrogen (CEE) (n=15), 1.0 mg/day of oral 17β estradiol (E2) (n=15), or 50 μg/day of transdermal 17βE2 (n=15) for 3 months. Subjects received either estrogen alone or with dydrogesterone at 5 mg/day. Plasma concentrations of sex hormone-binding globulin (SHBG), lipids, metallic ions, and derivatives of reactive oxygen metabolites (d-ROMs) were measured. RESULTS CEE, but not oral 17βE2, increased the plasma concentrations of triglyceride, copper (Cu), and d-ROMs and the ratio of small dense LDL/total LDL cholesterol, a marker for plasma distribution of small dense LDL. Transdermal 17βE2 decreased d-ROMs concentrations but did not significantly change other parameters. Plasma concentrations of SHBG increased in the 3 groups. Estrogen-induced changes in triglyceride correlated positively either with changes in SHBG (R=0.52, P=0.0002) or the ratio of small dense LDL/total LDL cholesterol (R=0.65, P<0.0001). Changes in Cu also correlated positively either with changes in SHBG (R=0.85, P<0.0001) or d-ROMs (R=0.86, P<0.0001). CONCLUSION The hepatic effects of different routes or types of estrogen therapy may be associated with plasma distribution of small dense LDL and free radical production in postmenopausal women.