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The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease.

ABSTRACT: BACKGROUND:The arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE?+?IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease. METHODS:Healthy perimenopausal and early postmenopausal women, ages 45 to 60 years, were enrolled in this randomized, double-blind, placebo-controlled trial. Women were randomized to receive TE (0.1 mg/day)?+?IMP (200 mg/day for 12 days) or identical placebo patches and pills for 12 months. Outcomes included: change in stress reactivity composite z-score (combining inflammatory, cortisol, and hemodynamic responses to a standardized psychological laboratory stressor); flow-mediated dilation (FMD) of the brachial artery (an index of vascular endothelial function); baroreflex sensitivity; and metabolic risk (presence of the metabolic syndrome or insulin resistance), all assessed at baseline and at months 6 and 12. RESULTS:Of 172 women enrolled, those assigned to TE?+?IMP tended to have higher resting baroreflex sensitivity than those assigned to placebo across the 6- and 12-month visits. Although treatment groups did not differ in terms of the other prespecified outcomes, a significant treatment-by-age interaction was found for FMD and stress reactivity such that an age-related decrease in FMD and increase in stress reactivity were seen among women assigned to placebo but not those assigned to TE?+?IMP. Women on TE?+?IMP also had lower resting diastolic blood pressure, lower levels of low-density lipoprotein cholesterol, and higher baroreflex sensitivity during stress testing. CONCLUSIONS:TE?+?IMP tended to improve cardiac autonomic control and prevented age-related changes in stress reactivity and endothelial function among healthy perimenopausal and early postmenopausal women.

SUBMITTER: Gordon JL

PROVIDER: S-EPMC7096310 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease.

Gordon Jennifer L JL Rubinow David R DR Watkins Lana L Hinderliter Alan L AL Caughey Melissa C MC Girdler Susan S SS

The Journal of clinical endocrinology and metabolism 20200501 5

<h4>Background</h4>The arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE + IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease.<h4>Methods</h4>Healthy perimenopausal and early postmenopausal women, ages 45 to 60 years, were enrolled in this randomized, double-blind, placebo-controlled trial. Women were ran ...[more]

PMID: 31838497

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Project description:ImportanceThe menopause transition and early postmenopausal period are associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms. Although a few studies suggest that hormone therapy can effectively manage existing depression during this time, to our knowledge, there have been no studies testing whether hormone therapy can prevent the onset of perimenopausal and early postmenopausal depressive symptoms.ObjectiveTo examine the efficacy of transdermal estradiol plus intermittent micronized progesterone (TE+IMP) in preventing depressive symptom onset among initially euthymic perimenopausal and early postmenopausal women. A secondary aim was to identify baseline characteristics predicting TE+IMP's beneficial mood effects.Design, setting, and participantsDouble-blind, placebo-controlled randomized trial at the University of North Carolina at Chapel Hill from October 2010 to February 2016. Participants included euthymic perimenopausal and early postmenopausal women from the community, aged 45 to 60 years.InterventionsTransdermal estradiol (0.1 mg/d) or transdermal placebo for 12 months. Oral micronized progesterone (200 mg/d for 12 days) was also given every 3 months to women receiving active TE, and identical placebo pills were given to women receiving placebo.Main outcome measuresScores on the Center for Epidemiological Studies-Depression Scale (CES-D), assessed at baseline and months 1, 2, 4, 6, 8, 10, and 12 after randomization, and the incidence of clinically significant depressive symptoms, defined as a CES-D score of at least 16.ResultsOf 172 participants, 130 were white (76%), and 70 were African American (19%), with a mean household income of $50 000 to $79 999. The mean age was 51 years, and 43 developed clinically significant depressive symptoms. Women assigned to placebo were more likely than those assigned to TE+IMP to score at least 16 on the CES-D at least once during the intervention phase (32.3% vs 17.3%; odds ratio [OR], 2.5; 95% CI, 1.1-5.7; P = .03) and had a higher mean CES-D score across the intervention period (P = .03). Baseline reproductive stage moderated the effect of treatment (β, -1.97; SEM, 0.80; P for the interaction = .03) such that mood benefits of TE+IMP vs placebo were evident among women in the early menopause transition (β, -4.2; SEM, 1.2; P < .001) but not the late menopause transition (β, -0.9; SEM, 0.3; P = .23) or among postmenopausal women (β, -0.3; SEM, 1.1; P = .92). Stressful life events in the 6 months preceding enrollment also moderated the effect of treatment on mean CES-D score such that the mood benefits of TE+IMP increased with a greater number of events (β, 1.22; SEM, 0.40; P = .003). Baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not moderate treatment effects.ConclusionsTwelve months of TE+IMP were more effective than placebo in preventing the development of clinically significant depressive symptoms among initially euthymic perimenopausal and early postmenopausal women.Trial registrationclinicaltrials.gov Identifier: NCT01308814.

Project description:The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years.A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45?mg (n?=?230) or transdermal estradiol (t-E2) 50??g (n?=?225; both with micronized progesterone 200?mg for 12 d each mo), or placebos (PBOs; n?=?275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact ? tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling.Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P?<?0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P?=?0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P?=?0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity.Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

Project description:Much attention has been drawn to the deleterious effects of adding progestins to estrogen as hormone therapy (HT) in postmenopausal women. Some widely prescribed progestins have been shown to partially oppose the beneficial effects of estrogens on surrogate markers of cardiovascular disease (CVD) risk. Progestins with higher androgenic activity may interfere with lipid profile and glucose tolerance, and could affect mechanisms of estrogen-induced C-reactive protein (CRP) stimulation. Recent data have shown that norpregnane derivatives, but not micronized progesterone, increase the risk of venous thromboembolism among transdermal estrogens users. The aim of the present study was to assess the effects of combining micronized progesterone with non-oral estrogen therapy on lipid profile and cardiovascular risk factors in a sample of early postmenopausal women.Clinical trial including 40 women receiving intranasal 17? estradiol 3 mg/day for two months and 46 women receiving percutaneous 17? estradiol gel 1.5 mg/day for three months (E2). Both groups received an additional 200 mg/day of micronized progesterone by vaginal route 14 days/month (E2+P). Outcome measures included body weight, waist circumference, body mass index (BMI), lipid profile and ultra-sensitive C-reactive protein (usCRP) at baseline and during the E2 or E2+P portions of treatment.Mean age was 51±3 years. Mean time since menopause was 22.2±10 months. Most participants were overweight; HT did not change BMI. E2 and E2+P did not affect waist circumference and weight. Menopausal symptoms improved after HT. The effects of intranasal and percutaneous estradiol were similar, regardless of the addition of progesterone. Similarly, for the overall group of 86 women, micronized progesterone did not alter the response to E2. Blood pressure, glucose, insulin, HDL-c, triglycerides, and usCRP remained constant with or without micronized progesterone. Total cholesterol decreased after E2, and progesterone maintained this reduction. LDL-c levels were similar at baseline and with E2, and lower during E2+P in relation to baseline.Cyclic, short term exposure to vaginal micronized progesterone did not alter the metabolic and cardiovascular effects of non-oral E2 in early, apparently healthy, postmenopausal women.ClinicalTrials.gov NCT01432028.

Project description:Amniotic epithelial cells (AECs), an emerging source of extrafoetal stem cells, have recently attracted attention for their great regenerative potential. Since AEC amplifications are accompanied by the loss of their native epithelial phenotype and by the progressive reduction of relevant biological properties, the issue to be addressed is the development of effective culture protocols. In this context, recently, it has been demonstrated that progesterone (P4) supplementation during ovine AEC (oAEC) expansion could prevent the undesirable epithelial-mesenchymal transition (EMT). In contrast, there is no information to date on the role of the other pregnancy steroids in culture. With this aim, the present study has been designed to clarify the impact of estradiol (E2), alone or in combination with P4 (12.5??M and 25??M), during oAEC amplification. Steroid supplementations were assessed by testing oAEC proliferation, stemness, EMT, and osteogenic or chondrogenic plasticity. The results indicated that EMT can be prevented exclusively in the presence of high doses of P4, while it occurred rapidly in cells exposed to E2 as denoted by protein (cytokeratin-8 and alpha-SMA) and gene expression (vimentin and snail) profiles. Moreover, steroid exposure was able to influence highly oAEC plasticity. Particularly, P4-treated cells displayed a precommitment towards osteogenic lineage, confirmed by the upregulation of OCN, RUNX2, and the greater deposition of calcium nodules. Conversely, P4 exposure inhibited oAEC chondrogenic differentiation, which was induced in E2-treated cells as confirmed by the upregulation of chondrogenesis-related genes (SOX9, ACAN, and COL2A1) and by the accumulation of Alcian blue-positive extracellular matrix. Simultaneously, E2-treated cells remained unresponsive to osteogenic inductive stimuli. In conclusion, media supplementation with high doses of steroids may be adopted to modulate phenotype and plasticity during oAEC amplification. Relevantly, the osteo or chondro steroid-induced precommitment may open unprecedented cell-based therapies to face the unsolved orthopaedic issues related to osteochondral regeneration.

Dataset Information

The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease.

Publications

The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease.

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