Transdermal 17β-estradiol Research Articles

Availability, Usage, and Preferences of Estradiol and Progestogen Preparations for Puberty Induction from a Multicentral Perspective

Introduction: Natural oestrogen administration as oral or transdermal 17β-estradiol is recommended for pubertal induction in girls with hypogonadism. However, suitable low-dose formulations are not consistently available globally. This questionnaire study aimed to identify the current availability of oestrogen and progesterone preparations worldwide. Methods: Endorsed by the ESPE Turner Syndrome Working Group, the questionnaire targeted paediatric endocrinologists. Questions focused on accessibility of oral/transdermal 17β-estradiol and progestogen preparations. Responses were collected through a SurveyMonkey survey disseminated via ESPE channels, direct outreach, and conferences from June 2020 to December 2022. Results: Participation included 229 healthcare professionals from 45 countries. Oral and transdermal 17β-estradiol in adult dosage was highly accessible (86.5% and 84.3%), with transdermal administration the preferred form (62.8%). Most commonly available estradiol preparations included 50 μg patches (32 countries) and 1 or 2 mg tablets (65.8% and 71.1% countries). However, 0.5 mg 17β-estradiol tablets were available in only 20% of respondents from 8 countries. Patches delivering 14 or 25 μg/day of 17β-estradiol were available in 3 and 20 countries, respectively. Oral progestogen had widespread availability (96.0%) and preference (87.0%), while transdermal usage was limited to 15.2% of respondents. Conclusion: This study highlights global challenges in accessing suitable hormone preparations for female pubertal induction. In most countries, the lowest dose of the estradiol is 50 µg for patches and 2 mg for tablets. Appropriate low-dose 17β-estradiol tablets are much less available than low-dose patches. Our survey underscores the importance of adapting guidelines to local availability, and the need for improved accessibility to address these global disparities.

Effectiveness and Safety of Different Estradiol Regimens in Transgender Women (TREAT Study): Protocol for a Randomized Controlled Trial.

Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments used on postmenopausal women. While care is currently provided with the best available evidence, there is a critical gap in knowledge about the safest and most effective estradiol routes of administration for GAHT in transgender women; this statement is supported by the World Professional Association for Transgender Health on their Standards of Care for the Health of Transgender and Gender Diverse People, version 8. Furthermore, the reported rates of cardiometabolic adverse events in transgender women highlight the importance of investigating changes in lipoproteins, glucose, and insulin sensitivity, among other markers while receiving GAHT. This study aims to evaluate the degree of testosterone suppression achieved at 1, 6, and 12 months in treatment-naive transgender women when randomized to GAHT with estradiol and spironolactone as antiandrogens. As a secondary aim, this study will assess the treatment effect on metabolic and coagulation factors from baseline to 6 and 12 months after initiating GAHT. This is a prospective pilot, open-label, randomized clinical trial conducted at an adult transgender clinic in a tertiary medical center. The 3 treatment arms include once-daily sublingual 17-β estradiol, twice-daily sublingual 17-β estradiol, and transdermal 17-β estradiol. All participants received spironolactone as an antiandrogen. Transgender women aged 18 to 45 years who are being evaluated for the initiation of GAHT with 17-β estradiol and did not have a history of coagulopathy, cigarette smoking, liver disease, dyslipidemia requiring treatment, or use of gonadotropin-releasing hormone agonist were eligible to enroll. The main outcome is the total testosterone suppression at 1 and 6 months after the initiation of GAHT, and the secondary outcome is to assess treatment effect in a lipid panel; homeostatic model assessment for insulin resistance; coagulation factors II, IX, and XI; Von Willebrand factor; activated protein C resistance; protein C; and protein S at baseline, 6 months, and 12 months after therapy is initiated. This study was funded in March 2022, and enrollment concluded in August 2022. It was concluded in July 2023, and currently, the results are being analyzed for publication. The Transgender Estradiol Affirming Therapy (TREAT) study offers a rigorous and reproducible approach to answer important questions regarding GAHT in transgender women, specifically, the most effective 17-β estradiol regimen to suppress testosterone levels to 50 ng/dL, as currently recommended. ClinicalTrials.gov NCT05010707; https://clinicaltrials.gov/study/NCT05010707. DERR1-10.2196/53092.

Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17β-estradiol (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17β-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

Bone Health in Young Athletes: a Narrative Review of the Recent Literature.

The aim of this review is to discuss the most recent published scientific evidence regarding bone health in the pediatric athlete. Pediatric athletes commonly suffer from overuse injuries to the physes and apophyses, as well as bone stress injuries, for which magnetic resonance imaging grading of the severity of injuries may be useful in guiding return to sport. Adolescent athletes, particularly those who train indoors and during the winter season, are at risk for vitamin D deficiency, which has important implications for bone mineral density. However, the relationship between vitamin D status and traumaticfracture risk is still unclear. While the female athlete triad is a well-established condition, the current work has led to the recognition of parallel pathophysiology in male athletes, referred to as the male athlete triad. Recent evidence suggests that transdermal 17β-estradiol treatment in amenorrhoeic female athletes is an effective adjunctive treatment to improve bone mineral density in treatment of the female athlete triad. Young athletes are at risk for musculoskeletal injuries unique to the growing skeleton. Optimizing nutritional intake, particularly related to adequate vitamin D intake and prevention of the athlete triad, is critical to optimize bone health in the young athlete.

Hypogonadism in adolescent girls: treatment and long-term effects.

Hypogonadism in adolescent females presents as delayed puberty or primary amenorrhea. Constitutional delay of growth and puberty, hypogonadotropic hypogonadism and hypergonadotropic hypogonadism represent the principal differential diagnosis of delayed puberty. Girls with hypogonadism require hormone replacement therapy to initiate and sustain puberty. We aimed to provide a brief review concerning treatment for female adolescents with hypogonadism and further to focus on current data regarding long-term effects of therapy. The published studies and articles of the international literature were used regarding the approach to adolescent girls with hypogonadism. The aim of therapy is the development of secondary sexual characteristics and achievement of target height, body composition and bone mass, to promote psychosexual health and, finally, to maximize the potential for fertility. Hypogonadal females need long-term HRT, so it is of great importance to fully define risks and benefits of therapy. The optimal pubertal induction in women contains both estrogens and progesterone regimens. Different therapeutic options have been described over the years in the literature, but larger randomized trials are required in order to define the ideal approach. The latest acquisitions in the field seem to propose that transdermal 17β-estradiol and micronized progesterone present the most physiological formulations available for this purpose. Further studies and follow up are needed concerning the long-term effects of HRT in adolescents.

Coronary artery calcium and bone mineral density by serial CTA: Does menopausal hormone therapy modify the association?

IntroductionBoth osteoporosis and cardiovascular disease (CVD) increase in women after menopause. Estrogen deficiency is thought to be an underlying mechanism for both these conditions. MethodsHealthy menopausal women (n = 374, age 42–58 years) underwent cardiac CT scans over four years as participants in the Kronos Early Estrogen Prevention Study (KEEPS), a randomized, controlled trial to Women randomized to either oral conjugated equine estrogens (o-CEE, n = 104), transdermal 17β-estradiol (t-E2, n = 119) or placebo (n-115). CAC (Agatston units, AU), and BMD (mg/cm3) were measured from thoracic vertebrae at baseline and at the 4 years of the study using validated software. ANOVA and multiple linear regression analyzed the association between incident CAC or progression of CAC and BMD among the treatment groups. ResultsAt baseline 374 women, 40 participants with CAC >0 had greater decrements in BMD than the 334 participants with CAC = 0 at baseline, The average change in BMD in o-CEE group with CAC was −9.6 ± 13.3 versus −3.1 ± 19.5 in those with zero CAC, p = 0.0018. With t-E2, BMD changed by −11.7 ± 26.2 in those with CAC versus +5.7 ± 26.2 in the zero CAC group, p ≤ 0. 0001. Similarly in the 66 participants that showed progression of CAC >1, had more BMD loss, than those with stable CAC regardless of the treatment. ConclusionProgression of bone loss is reduced among women treated with o-CEE or t-E2. Progression of CAC is associated with greater BMD loss, a relationship that is differentially modified by t-E2 and o-CEE.

Physiologic Transdermal Estradiol Replacement Mimics Effects of Endogenous Estrogen on Bone Outcomes in Hypoestrogenic Women with Anorexia Nervosa.

Background: While physiologic estrogen replacement results in increases in areal bone mineral density (aBMD) in hypoestrogenic adolescent girls and young adult women with AN, data are lacking regarding its impact on measures of volumetric BMD (vBMD), bone geometry, and structure. Methods: 23 young women with anorexia nervosa (AN) and 27 normal-weight healthy controls (HC) between 14–25 years old were followed for 12 months. AN participants received transdermal 17β-estradiol (continuously) with 10 days of cyclic oral progesterone (100 mg daily) every month for the study duration (AN-E+). DXA was used to measure aBMD and body composition, high resolution peripheral quantitative CT (HRpQCT) to assess vBMD, bone geometry and structure at the distal radius and tibia, and microfinite element analysis to estimate strength. Results: Groups did not differ for age. Median baseline BMI z-scores were −1.13 (−1.58, −0.38) in AN-E+ vs. 0.08 (−0.40, 0.84) in HC (p < 0.0001). For most HRpQCT parameters and strength estimates, young women with AN receiving physiologic estrogen replacement demonstrated similar changes over 12 months as did normoestrogenic HC. Additionally, radial cortical tissue mineral density, cortical vBMD, and failure load increased (p = 0.01; p = 0.02; p = 0.004 respectively) over 12 months in AN-E+ compared to HC. Conclusions: With physiologic estrogen replacement, bone accrual improved in AN to approximate changes observed in normoestrogenic controls followed without any intervention, with additional benefits observed for cortical tissue mineral density, cortical vBMD, and failure load at the radius in AN vs. controls. Thus, this strategy for estrogen replacement effectively mimics the effects of endogenous estrogen on bone structure and estimated strength.

Hormone Concentrations in Transgender Women Who Self-Prescribe Gender Affirming Hormone Therapy: A Retrospective Study

Self-prescribed gender-affirming hormone therapy (GAHT) is common practice among transgender women, especially in resource-limited countries, yet the effectiveness of each GAHT regimen to achieve female range sex hormone concentrations is not known. To describe the use and sex hormone concentrations of various GAHT regimens among transgender women who self prescribe in Thailand. This was a retrospective study in a community-based setting. Five hundred and 27 records of transgender women taking GAHT who were receiving care at a community health center between January 1, 2018, and December 31, 2020 were included for the analysis. Blood total testosterone and estradiol concentration after at least a 6-month period of GAHT. Multiple GAHT regimens were identified including oral estradiol valerate (EV), transdermal 17β-estradiol gel, injectable EV with hydroxyprogesterone caproate, injectable estradiol benzoate with progesterone, oral EV with cyproterone acetate (CPA), and oral contraceptive pills (OCPs). The most common GAHT regimen used by 49.1% of the participants was OCPs that contained 0.035 mg of ethinyl estradiol and 2 mg of CPA. Only 25.2% of this group had female range testosterone concentrations (<50 ng/dL). Oral EV and CPA were used by 23.1% of the participants. Most of them used 12.5 mg of CPA and 47.7% of this group had female range testosterone concentrations. There was no statistical significance between mean testosterone concentrations in CPA 12.5 and 25 mg groups, (P = .086). The inadequate sex hormone levels found in these commonly self-prescribed GAHT regimens provide information regarding the efficacy and safety of GAHT regimens for health care providers working with transgender women in a community-based setting. This study reflected a real-world situation and provided hormonal profiles among transgender women taking self-prescribed GAHT. However, issues in recall, medical literacy, and adherence to the medication may limit the results. Combined hormonal contraceptive pill was a commonly used GAHT regimen in Thai transgender women who self prescribe GAHT. However, this regimen was not effective to decrease testosterone concentrations to the recommended range of less than 50 ng/dL. Overall, self-prescription of GAHT does not appear to be effective in reaching target sex hormone concentrations. Including health care providers in the prescription and monitoring of GAHT may be a more effective approach in the delivery of GAHT.

Pubertal induction in girls with Turner Syndrome.

Turner Syndrome (TS) is the most common female sex chromosome aneuploidy in females, and patients may present with hypergonadotropic hypogonadism due to gonadal dysgenesis. Timing and modalities of pubertal induction in these patients is still a matter of debate. Aim of this review was to focus on the latest update on pubertal induction in TS. Based on literature data, the following practical approach to this issue is recommended. Pubertal induction should begin between 11 and 12 years of age, starting with low doses of estradiol to preserve height potential. Transdermal 17β-Estradiol (17β-E2) could represent the first-choice induction regimen as it is more physiologic compared to an oral regimen and avoids the first-pass mechanism in the liver. In the case of poor compliance, administration of oral 17β-E2 or ethinyl estradiol could be offered. Incremental dose increases, approximately every 6 months, can contribute to mimic normal pubertal progression until adult dosing is reached over a 2- to 3-year period. Progestin should be added once breakthrough bleeding occurs or after 2 to 3 years of estrogen therapy or if ultrasound shows a mature uterus with thick endometrium. Treatment needs to be individualized and monitored by clinical assessment in relation to patient compliance and satisfaction. Well-designed prospective randomized clinical trials aimed to identify the best estrogen regimen for pubertal induction in TS girls are needed.

Sleep quality and cortical amyloid-β deposition in postmenopausal women of the Kronos early estrogen prevention study.

Hormone therapy improves sleep in menopausal women and recent data suggest that transdermal 17β-estradiol may reduce the accumulation of cortical amyloid-β. However, how menopausal hormone therapies modify the associations of amyloid-β accumulation with sleep quality is not known. In this study, associations of sleep quality with cortical amyloid-β deposition and cognitive function were assessed in a subset of women who had participated in the Kronos early estrogen prevention study. It was a randomized, placebo-controlled trial in which recently menopausal women (age, 42-58; 5-36 months past menopause) were randomized to (1) oral conjugated equine estrogen (n = 19); (2) transdermal 17β-estradiol (tE2, n = 21); (3) placebo pills and patch (n = 32) for 4 years. Global sleep quality score was calculated using Pittsburgh sleep quality index, cortical amyloid-β deposition was measured with Pittsburgh compound-B positron emission tomography standard uptake value ratio and cognitive function was assessed in four cognitive domains 3 years after completion of trial treatments. Lower global sleep quality score (i.e., better sleep quality) correlated with lower cortical Pittsburgh compound-B standard uptake value ratio only in the tE2 group (r = 0.45, P = 0.047). Better global sleep quality also correlated with higher visual attention and executive function scores in the tE2 group (r = -0.54, P = 0.02) and in the oral conjugated equine estrogen group (r = -0.65, P = 0.005). Menopausal hormone therapies may influence the effects of sleep on cognitive function, specifically, visual attention and executive function. There also appears to be a complex relationship between sleep, menopausal hormone therapies, cortical amyloid-β accumulation and cognitive function, and tE2 formulation may modify the relationship between sleep and amyloid-β accumulation.

Sublingual Estradiol Is Associated with Higher Estrone Concentrations than Transdermal or Injectable Preparations in Transgender Women and Gender Nonbinary Adults.

Purpose: Serum hormone profiles among different feminizing gender-affirming hormone therapies (GAHT) are poorly characterized. To address this gap, we described the serum estrogen profiles of three 17β-estradiol preparations, taken with or without an antiandrogen, using a novel liquid chromatography-mass spectrometry (LC-MS/MS) assay in adults taking feminizing GAHT. Methods: This was a secondary analysis of 93 healthy transgender women and gender nonbinary adults taking feminizing GAHT in a prospective cross-sectional study. Eligible participants took 17β-estradiol (sublingual tablet, transdermal patch, or intramuscular/subcutaneous injection) with or without oral spironolactone for ≥12 months before study entry. We determined serum estrone and estradiol concentrations for each hormone preparation and described the association between estrone and (1) clinically relevant estradiol concentration ranges (≤200 and >200 pg/mL) and (2) antiandrogen use. To achieve our objectives, we described our protocol for developing an LC-MS/MS assay to measure estrone and estradiol concentrations. Results: Estrone concentrations were higher among participants taking sublingual 17β-estradiol tablets compared with transdermal or injectable preparations (p < 0.0001). Estradiol concentrations were higher for injectable versus transdermal preparations (p = 0.0201), but both were similar to sublingual tablet concentrations (p > 0.05). Estradiol >200 pg/mL (vs. ≤200 pg/mL) was associated with higher estrone concentrations among participants taking sublingual 17β-estradiol, but not transdermal or injectable 17β-estradiol. We observed no association between spironolactone and estrone concentrations (p > 0.5). Conclusion: Estrone concentrations were higher among transgender women and gender nonbinary adults taking sublingual 17β-estradiol compared with transdermal or injectable preparations. The role of estrone in clinical monitoring and the influence of other antiandrogens (e.g., cyproterone acetate) on the estrogen profile remain to be determined.

Peripheral Markers of Neurovascular Unit Integrity and Amyloid-β in the Brains of Menopausal Women.

Background:The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer’s disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers.Objective:This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women.Methods:A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n = 29), transdermal 17β-estradiol (tE2; n = 21), or oral conjugated equine estrogen (oCEE; n = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1–42 (Aβ1–42), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs.Results:Only the number of microvesicles positive for Aβ1–42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p = 0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p = 0.045).Conclusion:Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition.

Pubertal induction in girls with Turner syndrome

Turner Syndrome (TS) is the most common female sex chromosome aneuploidy in females, and patients may present with hypergonadotropic hypogonadism due to gonadal dysgenesis. Timing and modalities of pubertal induction in these patients is still a matter of debate. Aim of this review was to focus on the latest update on pubertal induction in TS. Based on literature data, the following practical approach to this issue is recommended. Pubertal induction should begin between 11 and 12 years of age, starting with low doses of estradiol to preserve height potential. Transdermal 17β-Estradiol (17β-E2) could represent the first-choice induction regimen as it is more physiologic compared to an oral regimen and avoids the first-pass mechanism in the liver. In the case of poor compliance, administration of oral 17β-E2 or ethinyl estradiol could be offered. Incremental dose increases, approximately every 6 months, can contribute to mimic normal pubertal progression until adult dosing is reached over a 2- to 3-year period. Progestin should be added once breakthrough bleeding occurs or after 2 to 3 years of estrogen therapy or if ultrasound shows a mature uterus with thick endometrium. Treatment needs to be individualized and monitored by clinical assessment in relation to patient compliance and satisfaction. Well-designed prospective randomized clinical trials aimed to identify the best estrogen regimen for pubertal induction in TS girls are needed.

Effect of menopausal hormone therapy on proteins associated with senescence and inflammation.

BackgroundEstrogen may inhibit cell senescence that contributes to age‐related disorders.This study determined the effects of menopausal hormone treatments on circulating levels of markers of cell senescence.MethodsGrowth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum using multiplexed bead‐based assays and compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17β‐estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization using the Wilcoxon rank sum test.ResultsSerum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. The difference in levels between treatment and placebo for GDF15, TNFR1, and FAS were greater for oCEE [−108 pg/mL (p = .008), −234 pg/mL (p = .0006), and −1374 pg/mL (p < .0001), respectively] than for tE2 [−76 pg/mL (p = .072), −105 pg/mL (p = .076), and −695 pg/mL (p = .036), respectively]. Additionally, TNFR1 showed a positive association with time past menopause (correlation = 0.255, p = .019).ConclusionsCirculating levels of some markers of cell senescence were lower in menopausal women treated with oCEE and tE2 compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery. These data generate new hypotheses with regard to the effects of menopause on the biology of aging.

Heart fat and carotid artery atherosclerosis progression in recently menopausal women: impact of menopausal hormone therapy: The KEEPS trial

Heart fat deposition has been linked to atherosclerosis, and both accelerate after menopause. Hormone therapy (HT) may differentially slow heart fat deposition and progression of atherosclerosis, depending on the specific HT agent or its route of administration. Our objective was to evaluate the effects of different HT agents, oral and transdermal, on associations between heart fat accumulation and atherosclerosis progression, measured by carotid intima-media thickness (CIMT), in recently menopausal women from the Kronos Early Estrogen Prevention Study (KEEPS) trial. KEEPS was a randomized, placebo-controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens (o-CEE) or 50 mcg/d transdermal 17β-estradiol (t-E2), compared with placebo, on 48 months progression of CIMT. Epicardial adipose tissue (EAT) and paracardial adipose tissue (PAT) volumes were quantified by computed tomography. In all, 467 women (mean age [SD] 52.7 [2.5]; 78.2% White; 30% on o-CEE, 30.8% t-E2, 39.2% placebo) with heart fat volumes and CIMT at baseline and 48 months were included. EAT and PAT changes were not associated with CIMT progression; however, the assigned treatment significantly modified the association between PAT (but not EAT) change and CIMT progression. In the o-CEE group, adjusted CIMT progression was 12.66 μm (95% confidence interval [CI] 1.80, 23.52) lower than in t-E2 group (P = 0.02), and 10.09 μm (95% CI 0.79, 19.39) lower than in placebo group (P = 0.03), as per 1-SD increase in PAT. Compared with t-E2, o-CEE appears to slow down the adverse effect of increasing PAT on progression of atherosclerosis. Whether this beneficial association is specific to CEE or to the oral route of CEE administration is unclear and should be assessed further.

Menopausal hormone therapy, blood thrombogenicity, and development of white matter hyperintensities in women of the Kronos Early Estrogen Prevention Study.

Development of white matter hyperintensities (WMH) in the brain is associated with blood thrombogenicity in recently menopausal women. This study examined the influence of menopausal hormone treatments (MHTs) on this association. Measures of blood thrombogenicity were examined in women of the Kronos Early Estrogen Prevention Study (n = 95) who had brain magnetic resonance imaging before and during the 48 months of randomization to transdermal 17β-estradiol (n = 30), oral conjugated equine estrogen (n = 29) both with progesterone for 12 days per month or placebo pills and patch (n = 36). Principal components (PCs) analysis was used to reduce the dimensionality of 14 markers of platelet activation and blood thrombogenicity. The first 5 PCs were assessed for association with treatment and changes in WMH. Within-person slopes were obtained to capture the extent of WMH change for each woman. WMH increased in all groups over the 48 months (P = 0.044). The partial effect of PC1, representing an average of six thrombogenicity variables (microvesicles derived from endothelium, leukocytes, and monocytes, and positive for tissue factor and adhesion molecules) on WMH was significant (P = 0.003). PC3, reflecting a contrast of platelet microaggregates and adenosine triphosphate secretion versus total platelet count, differed across groups (P = 0.006) with higher scores in the oral conjugated equine estrogen group. The global association between PCs and WMH increase, however, did not differ significantly by MHT (P = 0.207 for interaction between MHT and PC's). In recently menopausal women, the type of MHT did not significantly influence the association of markers of blood thrombogenicity with development of WMH in the brain.

Impact of menopausal hormone formulations on pituitary-ovarian regulatory feedback.

Changes in pituitary-ovarian hormones across the menopausal transition have multiple physiological consequences. However, little is known about how the major types of postmenopausal hormone therapy (HT) affect pituitary-ovarian hormonal relationships. This study evaluated these relationships in recently menopausal women (52.45 ± 2.49 yr of age) in the Kronos Early Estrogen Prevention Study (KEEPS) who were compliant to randomized, double-blinded treatment with oral conjugated equine estrogen (o-CEE; n = 109), transdermal 17β-estradiol (t-E2; n = 107), or placebo (n = 146). Androstenedione, testosterone, 17β-estradiol, estrone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum before (baseline) and 48 mo after randomization to treatment. Descriptive summaries of hormone levels were performed, and multiple regression analyses were used to examine the effects of o-CEE, t-E2, and placebo on these hormone levels at 48 mo, adjusting for baseline levels. A network analysis examined the covariance of changes in hormone levels over the 48 mo within treatment groups. As expected, at 48 mo of treatment, hormone levels differed between women in the two active treatment groups compared with placebo, and network analysis indicated stronger relationships among hormone levels in the t-E2 and o-CEE groups compared with placebo. Associations among testosterone, 17β-estradiol, FSH, and LH differed between the o-CEE group compared with t-E2 and placebo groups. Thus, two common HT regimens differentially alter pituitary-ovarian hormone levels, altering feedback cycles and interhormonal associations in recently menopausal women. These interactions provide the basis for future studies investigating the impact of hormonal modulation of aging, including cognitive decline in women.

Effects of Estrogen Replacement on Bone Geometry and Microarchitecture in Adolescent and Young Adult Oligoamenorrheic Athletes: A Randomized Trial.

Oligoamenorrheic athletes (OAs) have lower bone mineral density (BMD) and greater impairment of bone microarchitecture, and therefore higher fracture rates compared to eumenorrheic athletes. Although improvements in areal BMD (aBMD; measured by dual-energy X-ray absorptiometry) in OAs have been demonstrated with transdermal estrogen treatment, effects of such treatment on bone microarchitecture are unknown. Here we explore effects of transdermal versus oral estrogen versus no estrogen on bone microarchitecture in OA. Seventy-five OAs (ages 14 to 25 years) were randomized to (i) a 100-μg 17β-estradiol transdermal patch (PATCH) administered continuously with 200 mg cyclic oral micronized progesterone; (ii) a combined 30 μg ethinyl estradiol and 0.15 mg desogestrel pill (PILL); or (iii) no estrogen/progesterone (NONE) and were followed for 12 months. Calcium (≥1200 mg) and vitamin D (800 IU) supplements were provided to all. Bone microarchitecture was assessed using high-resolution peripheral quantitative CT at the distal tibia and radius at baseline and 1 year. At baseline, randomization groups did not differ by age, body mass index, percent body fat, duration of amenorrhea, vitamin D levels, BMD, or bone microarchitecture measurements. After 1 year of treatment, at the distal tibia there were significantly greater increases in total and trabecular volumetric BMD (vBMD), cortical area and thickness, and trabecular number in the PATCH versus PILL groups. Trabecular area decreased significantly in the PATCH group versus the PILL and NONE groups. Less robust differences between groups were seen at the distal radius, where percent change in cortical area and thickness was significantly greater in the PATCH versus PILL and NONE groups, and changes in cortical vBMD were significantly greater in the PATCH versus PILL groups. In conclusion, in young OAs, bone structural parameters show greater improvement after 1 year of treatment with transdermal 17β-estradiol versus ethinyl estradiol-containing pills, particularly at the tibia. © 2019 American Society for Bone and Mineral Research.

Transdermal estradiol for postpartum depression: results from a pilot randomized, double-blind, placebo-controlled study.

Postpartum depression (PPD) is a common complication following delivery, though evidence-based treatment options are limited. This study explores the feasibility and efficacy of outpatient PPD treatment with transdermal estradiol (TE). In a pilot, double-blind, placebo-controlled trial, women with PPD were randomized to receive transdermal 17β-estradiol (100mcg/day) or placebo patch. Over 6weeks, women completed weekly ratings on the Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS), and Hamilton Depression Scale (HAM-D). Primary outcome measures were treatment response (> 50% decrease from baseline BDI) and remission (BDI < 10) at 6weeks, and secondary outcome measures included severity on all scales at weeks 3 and 6. Of 12 recruited women, 6 received TE and 6 received placebo. By week 6, 5 women receiving TE responded to treatment and 4 showed symptom remission, compared to 2 responders and 1 remitter in the placebo group. This difference was not significant (p = 0.24). In a mixed-model of BDI ratings, TE was associated with a 9.2 point decrease at 3weeks (95%CI - 19.5 to + 1.0, p = 0.074) and a 10.5 point decrease at 6weeks (95%CI - 21.0-0.0, p = 0.049) compared to placebo, though these differences did not survive multiple comparisons correction. Analogous effects were found for HAM-D but not EPDS scores. Interestingly, no significant difference in plasma estradiol levels existed between groups. We were unable to demonstrate a significant therapeutic benefit of TE compared with placebo in PPD. Although limited by under-recruitment and loss to follow-up, our results suggest TE is a feasible option for outpatient PPD management, with preliminary evidence (based on secondary outcomes) for efficacy. Therapeutic effects may be seen as early as 3weeks and may not directly depend on peripheral measures of estradiol.

SUN-535 Impact of Route of Estrogen Administration on Bone Turnover Markers in Oligoamenorrheic Athletes and Mediators of these Effects

Transdermal, but not oral, estrogen replacement improves bone mineral density (BMD) in athletes with oligo-amenorrhea (OA). Our objective was to determine mechanisms that may explain the impact of route of estrogen administration on bone outcomes. Whereas IGF-1 is bone anabolic, sclerostin, preadipocyte factor-1 (Pref-1) and brain derived neurotropic factor (BDNF) inhibit bone formation, and an effect of estrogen on these factors has been demonstrated in other populations. However, few studies have examined the impact of route of estrogen administration on these factors in adolescents and young adults. Further, it is unclear how the route of estrogen administration impacts bioavailable testosterone, which in turn may impact bone outcomes in young oligo-amenorrheic women. 73 OA 14-25 years old received (i) a 17β-estradiol transdermal patch continuously with cyclic oral micronized progesterone (PATCH), (ii) a combined ethinyl estradiol and desogestrel pill (PILL), or (iii) no estrogen/progesterone (NONE) for 12-months. We evaluated fasting morning levels of a marker of bone formation [N-terminal propeptide of type 1 procollagen (P1NP)], a marker of bone resorption [N-telopeptide (NTX)], IGF-1, insulin-like growth factor binding protein 3 (IGFBP3), total testosterone, estradiol, sex hormone-binding globulin (SHBG), sclerostin, Pref-1, BDNF, calcium, 25(OH) vitamin D, and parathyroid hormone (PTH) at baseline and 12-months. Groups did not differ for age, weight, exercise activity or markers of bone formation at baseline. We have previously reported increases in areal BMD Z-scores at the spine and femoral neck in the PATCH compared to PILL and NONE groups (Ackerman et al: BJSM Oct. 2018). Over 12 months, between group analysis showed greatest decreases of P1NP in the PILL group (p=0.03) associated with a decrease in IGF-1 and IGF1/IGFBP-3 ratio (r=0.33, p≤0.05), and an increase in SHBG (r=-0.28;p=0.02). Within group analysis showed that sclerostin, Pref-1 and BDNF decreased in the PATCH group over 12 months (p=0.01, 0.01 and 0.04 respectively). PATCH group had the greatest increases in estradiol (p=0.0009), and estradiol increases were associated with increases in BMD. Groups did not differ for changes in NTX. Transdermal 17β-estradiol does not cause the decrease in IGF-1 and SHBG observed with oral ethinyl estradiol. It leads to decreases in sclerostin, Pref-1 and BDNF. These effects may mediate the beneficial effects of transdermal estrogen on bone in young women.