Discontinuation of Postmenopausal Hormone Therapy: Impact on the Cardiovascular System and Quality of Life

Study Overview
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Brief Summary
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Although the impact of postmenopausal hormone therapy (HT) on cardiovascular disease risk has been studied in several large randomized trials, little is known about the acute cardiovascular consequences of HT discontinuation. In this randomized, double-blind, placebo-controlled trial, the investigators will compare the cardiovascular consequences of abrupt and tapered modes of HT discontinuation in 150 Finnish healthy postmenopausal women under age 60 years. The primary outcome is brachial artery flow-mediated dilatation. In addition, biochemical markers will be measured during the study period of 20 weeks. Health-related quality of life, frequency of hot flush recurrence and other menopausal symptoms will be also assessed in these groups. The trial will provide new high-quality information about the cardiovascular safety as well as the correct timing and method of HT discontinuation.

Official Title
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Randomized Comparative Trial Between Abrupt and Tapered Discontinuation of Postmenopausal Hormone Therapy: Impact on Endothelial Function, Recurrence of Vasomotor Symptoms and Quality of Life

Conditions
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Menopause, Atherosclerosis, Cardiovascular Diseases, Estrogen Replacement Therapy

Intervention / Treatment
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* Drug: Estradiol
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: healthy postmenopausal women age ≤ 60 years has used postmenopausal hormone therapy for at least 3 years Exclusion Criteria: any clinically significant disease use of regular medication history of cardiovascular events history of smoking body mass index over 30 kg/m2 thickness of endometrium over 6 millimeters

Ages Eligible for Study
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Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group A, Abrupt Discontinuation<br>Women in group A will discontinue HT (estradiol, 2 mg daily) abruptly after study week 9 and will continue with placebo for study weeks 10-20. | Drug: Estradiol<br>* Active intervention is estradiol. Hormone therapy (HT) of all 150 participants will be standardized to 2.0 mg of oral estradiol (E2) without progestogen for six weeks prior to randomization. After that participants will be randomized into three groups (A, B, C) of equal size.<br>Other: Placebo<br>* Those in groups A and B will switch from estradiol to placebo at the beginning of the 10th week after abrupt or tapered discontinuation of HT.<br>|
| Other: Group B, Tapered Discontinuation<br>Women in group B will discontinue HT (estradiol, 2 mg daily) gradually during study weeks 7-9, as follows: weeks 7-9: 1 mg estradiol daily for 10 days and then 1 mg estradiol every other day for 11 days. weeks 10-20: placebo | Drug: Estradiol<br>* Active intervention is estradiol. Hormone therapy (HT) of all 150 participants will be standardized to 2.0 mg of oral estradiol (E2) without progestogen for six weeks prior to randomization. After that participants will be randomized into three groups (A, B, C) of equal size.<br>Other: Placebo<br>* Those in groups A and B will switch from estradiol to placebo at the beginning of the 10th week after abrupt or tapered discontinuation of HT.<br>|
| Active Comparator: Group C, Control Group<br>Women in Group C, the control group, will continue with HT (estradiol, 2 mg daily) throughout the whole study period of 20 weeks. | Drug: Estradiol<br>* Active intervention is estradiol. Hormone therapy (HT) of all 150 participants will be standardized to 2.0 mg of oral estradiol (E2) without progestogen for six weeks prior to randomization. After that participants will be randomized into three groups (A, B, C) of equal size.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brachial artery flow-mediated dilation (FMD) | The primary outcome in this study is brachial artery flow-mediated dilation (FMD) to assess endothelial function. To induce reactive hyperemia, a sphygmomanometer cuff is placed on the forearm and inflated to a suprasystolic pressure for five minutes, after which the cuff is deflated. The brachial artery diameter is measured at baseline and during reactive hyperemia, and the relative change in diameter (in millimeters) is calculated. We measure FMD at baseline (at study week 5) and after HT discontinuation (at study weeks 13 and 19). | 8 and 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptom diary | Participants will keep a symptom diary reporting the exact number, severity and timing of hot flashes during three periods each lasting three weeks: the first period at baseline, the second starting on the 10th week and the third starting on the 18th week. Based on the diary notes, we can assess, how frequent, severe and durable the symptoms are during each period. | 5 and 13 weeks | 
| Women's Health Questionnaire | Women's Health Questionnaire measures emotional and physical health. WHQ includes 37 questions that are answered based on the momentary feeling on a four-point scale (Yes, definitely; Yes, sometimes; No, not so much; No, not at all). The participant receives 37 points at minimum and 148 points at maximum. | 5 and 13 weeks | 
| Symptom questionnaire | The symptom questionnaire includes 19 questions about the frequency of menopausal symptoms (such as hot flashes, night sweats and insomnia) experienced during the past two weeks, and each question is evaluated on a four-point scale (never or seldom; once a month; once a week; almost daily).The participant receives 19 points at minimum and 76 points at maximum. | 5 and 13 weeks | 
| European Quality of Life Instrument | EuroQoL includes a health classification index that covers five dimensions of HRQL (mobility, self-care, usual activities, pain/discomfort, anxiety/depression).The participant receives 5 points at minimum and 15 points at maximum. In the second part of the questionnaire, there is a visual analogue scale ranging from 0, worst imaginable health state, to 100, best imaginable health state. Thus, the participant receives from 0 to 100 points from this part of the questionnaire. | 5 and 13 weeks | 
| Female Sexual Function Index | This questionnaire includes 19 questions about sexuality. The questions are answered on a five-point scale (almost always or always; most times; sometimes; a few times; almost never or never). The participant receives 19 points at minimum and 95 points at maximum. | 5 and 13 weeks | 
| Biomarker: Concentration of endothelin-1 | Concentration of endothelin-1 (ET-1, a vasoconstrictive marker, unit pmol/l) | 5 and 8 weeks | 
| Biomarker: Concentration of nitrite and nitrate | Concentration of nitrite and nitrate (markers of released nitric oxide and consequent vasodilation, unit µmol/l) | 5 and 8 weeks | 
| Biomarker: Concentration of Asymmetric Dimethylarginine | Concentration of asymmetric Dimethylarginine (ADMA, inhibitor of NO synthesis and indicator of endothelial dysfunction, unit µmol/l) | 5 and 8 weeks | 
| Biomarker: concentration of sex hormones | Concentration of sex hormones: Follicle-stimulating hormone (FSH, unit IU/l), luteinizing hormone (LH, unit IU/l), estrone (pmol/l), estradiol (nmol/l) and sex hormone-binding globulin (SHBG, unit nmol/l) | 2, 5 and 8 weeks | 
| Biomarker: Concentration of coagulation factors | Concentration of coagulation factors: fibrinogen (g/l), plasminogen activator inhibitor-1 (IU/ml), D-dimer (mg/l) | 5 and 8 weeks | 
| Biomarker: Concentration of lipids | Concentration of lipids: high-density lipoprotein cholesterol (HDL, unit mmol/l), low-density lipoprotein cholesterol (LDL, unit mmol/l), very low-density lipoprotein cholesterol (VLDL, unit mmol/l), triglycerides (mmol/l) and lipoprotein A (g/l) | 5 and 8 weeks | 
| Biomarker: Concentration of carbohydrate metabolism | Concentration of carbohydrate metabolism: fasting glucose (mmol/l) and insulin (mU/l) | 5 and 8 weeks | 
| Biomarker: Concentration of oxidative stress | Concentration of oxidative stress: oxidized LDL (U/l) | 5 and 8 weeks | 
| Biomarker: Concentration of inflammatory factors | Concentration of interferon-γ (IFN-γ, unit ng/ml), monocyte chemoattractant (MCP-1, unit pg/ml), macrophage inflammatory protein 1α (MIP-1α, unit pg/ml), tumor necrosis factor α (TNF-α, unit pg/ml) and high-sensitivity C-reactive protein (hs-CRP, unit mg/l) | 5 and 8 weeks | 
| Biomarker: Concentration of advanced glycation end products and soluble form of their receptor | Concentration of advanced glycation end products (AGE, unit U/ml) and soluble form of their receptor (sRAGE, unit pg/ml) | 5 and 8 weeks | 
| Biomarker: Concentration of cellular adhesion molecules | Concentration of cellular adhesion molecules: E selectin (mg/dl), intracellular cell-adhesion molecule-1 (ICAM-1, unit ng/ml), vascular cell adhesion molecule-1 (VCAM-1, unit ng/ml) | 5 and 8 weeks | 
| Concentration of matrix metalloproteinases | Concentration of matrix metalloproteinases (MMPs, unit µM) | 5 and 8 weeks | 
| Rey Auditory Verbal Learning Test (RAVLT) | RAVLT evaluates a wide diversity of cognitive functions. Participant is given a list of 15 unrelated words repeated over five different trials and are asked to repeat. Another list of 15 unrelated words are given and the client must again repeat the original list of 15 words and then again after 30 minutes. | 1 and 19 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized Controlled Trial, Menopause, Hormone Therapy, Vasomotor symptoms, Quality of Life, Cardiovascular diseases, Endothelium