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| ID | Type | Description | Link |
|---|---|---|---|
| R01AG024154 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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The purpose of this study is to examine the effects of oral 17B-estradiol (estrogen) on the progression of early (subclinical) atherosclerosis and cognitive decline in healthy postmenopausal women.
The primary hypothesis to be tested is that 17B-estradiol (estrogen) will reduce the progression of early atherosclerosis if initiated soon after menopause when the vascular endothelium (lining of blood vessels) is relatively healthy versus later when the endothelium has lost its responsiveness to estrogen. Ultrasonography will be used to measure the rate of change in the thickness of the carotid artery and cardiac computed tomography (CT) will be used to measure coronary artery calcium and coronary artery lesions. The second hypothesis to be tested is that 17B-estradiol (estrogen) will reduce the progression of cognitive decline if initiated soon after menopause when healthy brain tissue remains responsive to estrogen versus later when brain tissue has lost its responsiveness to estrogen.
A total of 643 (actual; 504 initially proposed) postmenopausal women were randomized according to their number of years since menopause, less than 6 years or 10 years or more, to receive either oral 17B-estradiol 1 mg daily or matching placebo. Women with a uterus will also use vaginal progesterone gel 4% (or placebo gel) the last ten days of each month. The vaginal progesterone will be distributed in a double-blinded fashion along with the randomized treatment so that only women exposed to active treatment will receive active progesterone. As initially proposed, participants will undergo ultrasonography at baseline and every 6 months throughout the 2 to 5 years (average 3 years) of randomized treatment. Participants will also undergo cognitive testing at baseline and after 3 years of randomized treatment. The trial has been extended for an additional 2 to 2.5 years of randomized treatment (overall average randomized treatment of 5 years and range of 2 to 8.5 years). Ultrasonography will continue to be collected every 6 months and upon completion of randomized treatment, participants will undergo cardiac CT for coronary artery calcium and coronary artery lesion measurements. Participants will also undergo a third cognitive testing at the completion of randomized treatment.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 17B-estradiol | Active Comparator | Oral 17B-estradiol 1 mg daily |
|
| Placebo | Placebo Comparator | Matching oral 17B-estradiol placebo daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 17B-estradiol | Drug | Oral 17B-estradiol 1 mg daily |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Progression of Subclinical Atherosclerosis | Rate of change in distal common carotid artery (CCA) far wall intima-media thickness (mm per year) in computer image processed B-mode ultrasonograms that were obtained at two baseline examinations (averaged to obtain the baseline CIMT value) and every 6 months during trial follow-up. | Baseline x 2 and then every 6 months up to 6.7 years |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Neurocognitive Function (Global Cognition) | All neuropsychological test scores at baseline and follow-up assessments were standardized ([raw score - mean score]/standard deviation) using the baseline means and standard deviations from the entire ELITE sample. Each of three cognitive composite scores was calculated at baseline and follow-up assessments as the weighted average of the individual donor standardized test scores, weighted by the inverse correlation among tests.The change from baseline (endpoint minus baseline cognitive outcome) was computed for each of the cognitive scores (verbal memory, global cognition, and executive functions). Since the outcome is not a single test but a weighted average of multiple tests, the range is not standard and not reported. Higher scores mean better outcomes. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Howard N. Hodis, M.D. | Atherosclerosis Research Unit, University of Southern California | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Atherosclerosis Research Unit, University of Southern California | Los Angeles | California | 90033 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25380275 | Background | Hodis HN, Mack WJ, Shoupe D, Azen SP, Stanczyk FZ, Hwang-Levine J, Budoff MJ, Henderson VW. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause. 2015 Apr;22(4):391-401. doi: 10.1097/GME.0000000000000343. | |
| 27028912 | Result | Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP; ELITE Research Group. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016 Mar 31;374(13):1221-31. doi: 10.1056/NEJMoa1505241. |
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2166 individuals were screened by telephone, 1,271 were ineligible. 895 individuals were screened in research clinic, 252 were excluded (133 did not meet inclusion criteria; 119 declined to participate). 643 individuals were randomized.
Participants were recruited from the general population through media campaigns.
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| ID | Title | Description |
|---|---|---|
| FG000 | Early Postmenopause 17B-estradiol | Early postmenopause, <6 years-since-menopause, Oral 17B-estradiol 1 mg daily |
| FG001 | Early Postmenopause Placebo | Early postmenopause, <6 years-since-menopause, Matching oral 17B-estradiol placebo daily |
| FG002 | Late Postmenopause 17B-estradiol | Late postmenopause, >10 years-since-menopause, Oral 17B-estradiol 1 mg daily |
| FG003 | Late Postmenopause Placebo | Late postmenopause, >10 years-since-menopause, Matching oral 17B-estradiol placebo daily |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Early Postmenopause 17B-estradiol | Early postmenopause, <6 years-since-menopause, Oral 17B-estradiol 1 mg daily |
| BG001 | Early Postmenopause Placebo | Early postmenopause, <6 years-since-menopause, Matching oral 17B-estradiol placebo daily |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Progression of Subclinical Atherosclerosis | Rate of change in distal common carotid artery (CCA) far wall intima-media thickness (mm per year) in computer image processed B-mode ultrasonograms that were obtained at two baseline examinations (averaged to obtain the baseline CIMT value) and every 6 months during trial follow-up. | Early postmenopause group (<6 years-since-menopause) at baseline and late postmenopause group (>10 years-since-menopause) at baseline. | Posted | Mean | 95% Confidence Interval | mm per year | Baseline x 2 and then every 6 months up to 6.7 years |
|
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Adverse events collected per intervention
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 17B-estradiol | Oral 17B-estradiol 1 mg daily | 1 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| aplastic anemia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| chest discomfort | General disorders | MedDRA (Unspecified) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Howard N. Hodis, M.D., Director, Atherosclerosis Research Unit | University of Southern California | 323-442-1478 | athero@usc.edu |
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| ID | Term |
|---|---|
| D050197 | Atherosclerosis |
| D002318 | Cardiovascular Diseases |
| D003324 | Coronary Artery Disease |
| ID | Term |
|---|---|
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D003327 | Coronary Disease |
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| ID | Term |
|---|---|
| D004958 | Estradiol |
| D004967 | Estrogens |
| D015914 | Estrogen Replacement Therapy |
| D020249 | Hormone Replacement Therapy |
| ID | Term |
|---|---|
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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| Placebo | Other | Matching oral 17B-estradiol placebo daily |
|
|
| Baseline and at 2.5 years and 5 years |
| Coronary Artery Calcium | Number of participants with coronary artery calcium measured by cardiac computed tomography | End of randomized treatment, up to 6.7 years |
| 27421538 | Result | Henderson VW, St John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, Kono N, Dustin L, Allayee H, Mack WJ. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology. 2016 Aug 16;87(7):699-708. doi: 10.1212/WNL.0000000000002980. Epub 2016 Jul 15. |
| 39980346 | Derived | Chen IJ, Stanczyk FZ, Sriprasert I, Karim R, Shoupe D, Kono N, Hodis HN, Mack WJ. Sex steroid hormones and subclinical atherosclerosis progression in postmenopausal women. Eur J Endocrinol. 2025 Mar 3;192(3):248-256. doi: 10.1093/ejendo/lvaf032. |
| 35526057 | Derived | Lin F, Pa J, Karim R, Hodis HN, Han SD, Henderson VW, St John JA, Mack WJ. Subclinical carotid artery atherosclerosis and cognitive function in older adults. Alzheimers Res Ther. 2022 May 7;14(1):63. doi: 10.1186/s13195-022-00997-7. |
| 34736575 | Derived | Sriprasert I, Mert M, Mack WJ, Hodis HN, Shoupe D. Use of oral estradiol plus vaginal progesterone in healthy postmenopausal women. Maturitas. 2021 Dec;154:13-19. doi: 10.1016/j.maturitas.2021.09.002. Epub 2021 Sep 5. |
| 32925623 | Derived | Sriprasert I, Kono N, Karim R, Hodis HN, Stanczyk FZ, Shoupe D, Mack WJ. Factors Associated With Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy. Obstet Gynecol. 2020 Oct;136(4):675-684. doi: 10.1097/AOG.0000000000004006. |
| 31362877 | Derived | Sriprasert I, Mack WJ, Hodis HN, Allayee H, Brinton RD, Karim R. Effect of ApoE4 Genotype on the Association Between Metabolic Phenotype and Subclinical Atherosclerosis in Postmenopausal Women. Am J Cardiol. 2019 Oct 1;124(7):1031-1037. doi: 10.1016/j.amjcard.2019.06.022. Epub 2019 Jul 15. |
| 30272234 | Derived | Sriprasert I, Hodis HN, Karim R, Stanczyk FZ, Shoupe D, Henderson VW, Mack WJ. Differential Effect of Plasma Estradiol on Subclinical Atherosclerosis Progression in Early vs Late Postmenopause. J Clin Endocrinol Metab. 2019 Feb 1;104(2):293-300. doi: 10.1210/jc.2018-01600. |
| 25405497 | Derived | Karim R, Stanczyk FZ, Brinton RD, Rettberg J, Hodis HN, Mack WJ. Association of endogenous sex hormones with adipokines and ghrelin in postmenopausal women. J Clin Endocrinol Metab. 2015 Feb;100(2):508-15. doi: 10.1210/jc.2014-2834. Epub 2014 Nov 18. |
| 19996872 | Derived | Henderson VW. Aging, estrogens, and episodic memory in women. Cogn Behav Neurol. 2009 Dec;22(4):205-14. doi: 10.1097/WNN.0b013e3181a74ce7. |
| Lost to Follow-up |
|
| Too busy |
|
| Moved from area |
|
| Did not want estradiol |
|
| Armed-services duty |
|
| Competing family issue |
|
| Physician Decision |
|
| Lost interest |
|
| Weight increase |
|
| Concern about blood clots |
|
| Breast cancer diagnosis on baseline mammogram |
|
| BG002 | Late Postmenopause 17B-estradiol | Late postmenopause, >10 years-since-menopause, Oral 17B-estradiol 1 mg daily |
| BG003 | Late Postmenopause Placebo | Late postmenopause, >10 years-since-menopause, Matching oral 17B-estradiol placebo daily |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
Matching oral 17B-estradiol placebo daily
|
|
| Secondary | Change in Neurocognitive Function (Global Cognition) | All neuropsychological test scores at baseline and follow-up assessments were standardized ([raw score - mean score]/standard deviation) using the baseline means and standard deviations from the entire ELITE sample. Each of three cognitive composite scores was calculated at baseline and follow-up assessments as the weighted average of the individual donor standardized test scores, weighted by the inverse correlation among tests.The change from baseline (endpoint minus baseline cognitive outcome) was computed for each of the cognitive scores (verbal memory, global cognition, and executive functions). Since the outcome is not a single test but a weighted average of multiple tests, the range is not standard and not reported. Higher scores mean better outcomes. | Sample size represents the number of participants with analyzable data collected at baseline, 2.5 years, and 5.0 years. Early postmenopause group (<6 years-since-menopause) at baseline and late postmenopause group (>10 years-since-menopause) at baseline. | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline and at 2.5 years and 5 years |
|
|
|
| Secondary | Coronary Artery Calcium | Number of participants with coronary artery calcium measured by cardiac computed tomography | CAC data was obtained in 380 participants. Participants who were not taking the study products at the last follow-up visit, who had adherence to the study regimen that was lower than 80%, or who had a CAC scan more than 6 months after the final study visit were not included in the analysis. Early postmenopause group (<6 years-since-menopause) at baseline and late postmenopause group (>10 years-since-menopause) at baseline. | Posted | Count of Participants | Participants | End of randomized treatment, up to 6.7 years |
|
|
|
| 323 |
| 43 |
| 323 |
| 216 |
| 323 |
| EG001 | Placebo | Matching oral 17B-estradiol placebo daily | 1 | 320 | 45 | 320 | 226 | 320 |
| unstable angina | Cardiac disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| atrial fibrillation | Cardiac disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| pleuropericarditis | Cardiac disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| myocardial infarction | Cardiac disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| veritgo | Ear and labyrinth disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| ischemic colitis | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| gastroesophageal reflux disease | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| illeitis | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| gastrointestinal hemorrhage | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| pancreatitis | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| death | General disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| non-cardiac chest pain | General disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| drug hypersensitivity | Immune system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| cellulitis | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| lobar pneumonia | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| pelvic abscess | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| pneumonia | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| cervical vertebral fracture | Injury, poisoning and procedural complications | MedDRA (Unspecified) | Systematic Assessment |
|
| femoral neck fracture | Injury, poisoning and procedural complications | MedDRA (Unspecified) | Systematic Assessment |
|
| foot fracture | Injury, poisoning and procedural complications | MedDRA (Unspecified) | Systematic Assessment |
|
| fracture | Injury, poisoning and procedural complications | MedDRA (Unspecified) | Systematic Assessment |
|
| systemic lupus erythematosus | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| B-cell lymphoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| breast cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| breast cancer in situ | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| colon adenoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| colorectal cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| gastric cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| glioblastoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| malignant peritoneal neoplasm | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| mycosis fungoides | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| ovarian epithelial cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| pancreatic carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| polycythemia vera | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| uterine cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (Unspecified) | Systematic Assessment |
|
| amnesia | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| dizziness | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| syncope | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| transient ischemic attack | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Suicide ideation | Psychiatric disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| psychotic disorder | Psychiatric disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| pulmonary embolism | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| spinal laminectomy | Surgical and medical procedures | MedDRA (Unspecified) | Systematic Assessment |
|
| deep vein thrombosis | Vascular disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| ulcerative colitis | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| non-cardiac chest pain | General disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| drug hypersensitivity | Immune system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| bronchitis | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| influenza | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| sinusitis | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| urinary tract infection | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| contusion | Injury, poisoning and procedural complications | MedDRA (Unspecified) | Systematic Assessment |
|
| fall | Injury, poisoning and procedural complications | MedDRA (Unspecified) | Systematic Assessment |
|
| road traffic accident | Injury, poisoning and procedural complications | MedDRA (Unspecified) | Systematic Assessment |
|
| arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| back pain | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| depression | Psychiatric disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| cervical dysplasia | Reproductive system and breast disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| vaginal discharge | Reproductive system and breast disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| vulvovaginal pruritis | Reproductive system and breast disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| cough | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| rash | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
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| D017202 |
| Myocardial Ischemia |
| D006331 | Heart Diseases |
| D011083 |
| Polycyclic Compounds |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045505 | Physiological Effects of Drugs |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D004358 | Drug Therapy |
| D013812 | Therapeutics |
| Late postmenopause group |
|
|
| Late postmenopause group |
|
|