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Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS).
Taylor, HS, Tal, A, Pal, L, Li, F, Black, DM, Brinton, EA, Budoff, MJ, Cedars, MI, Du, W, Hodis, HN, et al
JAMA internal medicine. 2017;(10):1471-1479
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Abstract
IMPORTANCE Sexual dysfunction, an important determinant of women's health and quality of life, is commonly associated with declining estrogen levels around the menopausal transition. OBJECTIVE To determine the effects of oral or transdermal estrogen therapy vs placebo on sexual function in postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS Ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS), a 4-year prospective, randomized, double-blinded, placebo-controlled trial of menopausal hormone therapy in healthy, recently menopausal women. Of 727 KEEPS enrollees, 670 agreed to participate in this multicenter ancillary study. Women were 42 to 58 years old, within 36 months from last menstrual period. Data were collected from July 2005 through June 2008 and analyzed from July 2010 through June 2017. INTERVENTIONS Women were randomized to either 0.45 mg/d oral conjugated equine estrogens (o-CEE), 50 µg/d transdermal 17β-estradiol (t-E2), or placebo. Participants also received 200 mg oral micronized progesterone (if randomized to o-CEE or t-E2) or placebo (if randomized to placebo estrogens) for 12 days each month. MAIN OUTCOMES AND MEASURES Aspects of sexual function and experience (desire, arousal, lubrication, orgasm, satisfaction, and pain) were assessed using the Female Sexual Function Inventory (FSFI; range, 0-36 points; higher scores indicate better sexual function). Low sexual function (LSF) was defined as an FSFI overall score of less than 26.55. Distress related to low FSFI score (required for the diagnosis of sexual dysfunction) was not evaluated. RESULTS The 670 participants had a mean (SD) age of 52.7 (2.6) years. The t-E2 treatment was associated with a significant yet moderate improvement in the FSFI overall score across all time points compared with placebo (average efficacy, 2.6; 95% CI, 1.11-4.10; adjusted P = .002). With o-CEE treatment, there was no significant difference in FSFI overall score compared with placebo (mean efficacy, 1.4; 95% CI, -0.1 to 2.8; adjusted P = .13). There was no difference in FSFI overall score between the t-E2 and o-CEE groups on average across 48 months (adjusted P = .22). In the individual domains of sexual function, t-E2 treatment was associated with a significant increase in mean lubrication (0.61; 95% CI, 0.25-0.97; P = .001) and decreased pain (0.67; 95% CI, 0.25-1.09; P = .002) compared with placebo. Overall, the proportion of women with LSF was significantly lower after t-E2 treatment compared with placebo (67%; 95% CI, 55%-77% vs 76%; 95% CI, 67%-83%; P = .04). For o-CEE there was no significant reduction in the odds of LSF. CONCLUSIONS AND RELEVANCE Treatment with t-E2 modestly improved sexual function in early postmenopausal women, but whether it relieved symptoms of distress is not known. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00154180.
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Factors determining the use of hormonal therapy and phytotherapy in Spanish postmenopausal women.
Mendoza, N, Hernández, C, Cornellana, MJ, Carballo, A, Llaneza, P, Harvey, X, Palacios, S, ,
Climacteric : the journal of the International Menopause Society. 2016;(4):375-80
Abstract
OBJECTIVE To identify women's sociodemographic and variables related to health care with the prescription of hormonal therapy (HT) and phytotherapy (PT) in Spanish postmenopausal women. METHOD The survey consisted of a multicenter, observational, cross-sectional, questionnaire-based investigation and was conducted among 3022 postmenopausal women. RESULTS Of all the women, 31.8% reported the use of systemic HT or PT sometime in their lives. Hot flushes and information received about menopause were the most important variables that influence HT and PT use, although far more intense symptoms were observed in those who were inclined to use HT. The use of HT or PT was more frequently reported among women with high levels of education, who came from private clinics and lived in urban areas. Women who had primary ovarian insufficiency or surgical menopause were inclined to use HT. CONCLUSION Hot flushes and information received about menopause are the most important variables that influence HT and PT use.
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Self-reported menopausal symptoms, coronary artery calcification, and carotid intima-media thickness in recently menopausal women screened for the Kronos early estrogen prevention study (KEEPS).
Wolff, EF, He, Y, Black, DM, Brinton, EA, Budoff, MJ, Cedars, MI, Hodis, HN, Lobo, RA, Manson, JE, Merriam, GR, et al
Fertility and sterility. 2013;(5):1385-91
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OBJECTIVE To determine whether self-reported menopausal symptoms are associated with measures of subclinical atherosclerosis. DESIGN Cross-sectional analysis. SETTING Multicenter, randomized controlled trial. PATIENT(S): Recently menopausal women (n = 868) screened for the Kronos Early Estrogen Prevention Study (KEEPS). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Baseline menopausal symptoms (hot flashes, dyspareunia, vaginal dryness, night sweats, palpitations, mood swings, depression, insomnia, irritability), serum E2 levels, and measures of atherosclerosis were assessed. Atherosclerosis was quantified using coronary artery calcium (CAC) Agatston scores (n = 771) and carotid intima-media thickness (CIMT). Logistic regression model of menopausal symptoms and E2 was used to predict CAC. Linear regression model of menopausal symptoms and E2 was used to predict CIMT. Correlation between length of time in menopause with menopausal symptoms, E2, CAC, and CIMT were assessed. RESULT(S): In early menopausal women screened for KEEPS, neither E2 nor climacteric symptoms predicted the extent of subclinical atherosclerosis. Palpitations and depression approached significance as predictors of CAC. Other symptoms of insomnia, irritability, dyspareunia, hot flashes, mood swings, night sweats, and vaginal dryness were not associated with CAC. Women with significantly elevated CAC scores were excluded from further participation in KEEPS; in women meeting inclusion criteria, neither baseline menopausal symptoms nor E2 predicted CIMT. Years since menopause onset correlated with CIMT, dyspareunia, vaginal dryness, and E2. CONCLUSION(S): Self-reported symptoms in recently menopausal women are not strong predictors of subclinical atherosclerosis. Continued follow-up of this population will be performed to determine whether baseline or persistent symptoms in the early menopause are associated with progression of cardiovascular disease. CLINICAL TRIAL REGISTRATION NUMBER NCT00154180.
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Which progestogen is more likely to increase the risk of fatal myocardial infarction: a combination of epidemiological and trial evidence.
Al-Azzawi, F, Thompson, J, Stevenson, J
Maturitas. 2006;(2):154-63
Abstract
OBJECTIVES To evaluate the impact of metabolic effects of different progestogens on the risk of fatal myocardial infarction is evaluated. METHODS The changes in (apo)lipoproteins obtained from a randomized trial of three hormone therapy regimens were applied to three models for predicting fatal myocardial infarction derived from the apolipoprotein-related mortality risk (AMORIS) study. In our trial, 487 postmenopausal women were randomized to oral estradiol, with sequential addition of two trimegestone (TMG) doses or norethisterone acetate (NETA), and studied at baseline and after 3, 6, and 12 months. RESULTS The change from baseline in risk of fatal myocardial infarction, using AMORIS model 3, containing total cholesterol, triglycerides, and apolipoprotein AI, was a 10% reduction for the two TMG doses; NETA had no apparent impact. The differences between treatments were significant at all three time points. When apoB was added in AMORIS model 4, the difference between treatments (5% reduction in the two doses of TMG, compared to NETA) decreased over time, probably due to the effect of dropouts in the NETA group. CONCLUSIONS This analysis shows different metabolic responses to progestogens in terms of risk of fatal myocardial infarction. Generalization of health benefits or adverse effects seen in trials of hormone therapy to other progestogens could be misleading.
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Bone response to treatment with lower doses of conjugated estrogens with and without medroxyprogesterone acetate in early postmenopausal women.
Lindsay, R, Gallagher, JC, Kleerekoper, M, Pickar, JH
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2005;(4):372-9
Abstract
Lower doses of conjugated estrogens (CE) alone or combined with lower doses of medroxyprogesterone acetate (MPA) increase mean bone mineral density (BMD) from baseline at the spine and hip in early postmenopausal women. However, not all women on therapy gain BMD. The incidence of continued bone loss (defined as a loss of BMD of > 2% from baseline) among women using lower doses of CE and CE/MPA is unknown. This randomized, double-blind, placebo-controlled, multicenter substudy of the Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) trial investigated the incidence of continued bone loss with lower-dose CE and CE/MPA. Eight hundred twenty-two healthy postmenopausal women with intact uteri received CE 0.625, CE 0.625/MPA 2.5, CE 0.45, CE 0.45/MPA 2.5, CE 0.45/MPA 1.5, CE 0.3, CE 0.3/MPA 1.5 (all doses in mg/day), or placebo for 2 years along with 600 mg/day of calcium. Changes from baseline in spine and total hip BMD were compared among treatment groups in an intent-to-treat analysis. At 12 months, < 10% of women on active treatment lost > 2% of spinal BMD (except CE 0.3/MPA 1.5 [15.6%]), compared with 41.2% of women on placebo. At 24 months, the percentages of women on active treatment who lost > 2% of spine BMD ranged from 4.5% with CE 0.45/MPA 1.5-15.6% with CE 0.3/MPA 1.5, compared with 55.2% of women taking placebo. More than 85% of women on active treatment did not experience continued BMD loss at the hip at 12 months and 24 months, in contrast to 30.6% of women on placebo at 12 months and 36.5% at 24 months. Women receiving active treatment who lost > 2% of spine or hip BMD also had a lesser reduction in biochemical markers of bone turnover. In summary, continued bone loss among early postmenopausal women treated with lower doses of CE or CE/MPA is uncommon.
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Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial.
Archer, DF, Thorneycroft, IH, Foegh, M, Hanes, V, Glant, MD, Bitterman, P, Kempson, RL
Menopause (New York, N.Y.). 2005;(6):716-27
Abstract
OBJECTIVE The purpose of this multicenter, double-blind, randomized, parallel-group study was to determine the effect of thirteen 28-day cycles of drospirenone combined with estradiol, compared with estradiol alone, on the endometrium of postmenopausal women. DESIGN Postmenopausal women not on hormone therapy but with an intact uterus were enrolled (N = 1,147); 1,142 were evaluated. Participants were randomly assigned to treatment with 1.0 mg of estradiol alone (E(2) monotherapy) or 1.0 mg of estradiol plus 0.5, 1.0, 2.0, or 3.0 mg of drospirenone (DRSP/E(2)). Endometrial biopsies were performed at baseline, at 7 months if indicated, and at study end in the 13th month. Safety was evaluated with peripheral blood samples for hematology, liver and renal function, and lipids, along with vital signs and interval medical evaluations. RESULTS When compared with estradiol alone, combinations of drospirenone and estradiol were effective in protecting against endometrial hyperplasia. The probability of hyperplasia was 0.060 (95% CI, 0.043-0.078) for the E(2) monotherapy group, 0.007 for the 2-mg DRSP/E(2) group, and nonsignificant for the remaining drospirenone/estradiol groups. Endometrial bleeding decreased in all treatment groups over time. The combination of drospirenone and E(2) relieved menopausal symptoms and resulted in improvements in health-related quality-of-life measures. There were no significant adverse events, and effects on triglycerides, total cholesterol, and high-density lipoprotein cholesterol were positive. CONCLUSIONS The use of drospirenone combined with estradiol provides protection against endometrial hyperplasia, reduces endometrial bleeding with time, and relieves menopausal symptoms. There were no safety issues and blood pressure was reduced in women with hypertension.
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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.
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Postmenopausal uterine bleeding profiles with two forms of continuous combined hormone replacement therapy.
Johnson, JV, Davidson, M, Archer, D, Bachmann, G
Menopause (New York, N.Y.). 2002;(1):16-22
Abstract
OBJECTIVE This study was designed to compare the bleeding profiles of conjugated equine estrogens 0.625 mg in combination with 2.5 mg medroxyprogesterone acetate (Prempro; CEE/MPA group), the most widely prescribed continuous combined hormone replacement therapy (CCHRT) in the United States, with 17beta-estradiol 1 mg combined with 0.5 mg norethindrone acetate (Activella; E(2)/NETA group), a newly available CCHRT preparation, over a 6-month period. DESIGN This study was a prospective, randomized, multicenter, double-blind, controlled trial. A total of 438 healthy postmenopausal women were randomized and received treatment (Activella n = 217, Prempro n = 221). Each woman recorded bleeding diaries daily. Total cholesterol, triglycerides, and endometrial biopsies were obtained at screening and end-of-trial visits. RESULTS The more favorable bleeding profile was found in the E(2)/NETA (Activella) group. The differences in bleeding patterns were most marked in the first 3 months of treatment in women who were 1-2 years from last menses, with no bleeding in 71.4% vs. 40.0%; ( p = 0.005) and with no bleeding and no spotting in 54.8% vs. 17.1%; (p = 0.001). Triglycerides fell by 8.5% in the E(2)/NETA group and increased by 11.7% in the CEE/MPA group (p < 0.001). Total cholesterol declined by 9.1% and 6.9%, respectively. CONCLUSION The most important factor in the continuation of HRT is uterine bleeding. E(2)/NETA has significantly less bleeding than the most commonly prescribed CCHRT CEE/MPA, therefore; E(2)/NETA should be associated with improved continuation rates. The patient taking E(2)/NETA will receive effective treatment for her menopausal symptoms with less bleeding.