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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
TRIPLE
Enrollment
150
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.
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.
HUS Women's Hospital
Helsinki, Finland
RECRUITINGBrachial 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).
Time frame: 8 and 14 weeks
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 5 and 13 weeks
Biomarker: Concentration of endothelin-1
Concentration of endothelin-1 (ET-1, a vasoconstrictive marker, unit pmol/l)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 5 and 8 weeks
Biomarker: Concentration of carbohydrate metabolism
Concentration of carbohydrate metabolism: fasting glucose (mmol/l) and insulin (mU/l)
Time frame: 5 and 8 weeks
Biomarker: Concentration of oxidative stress
Concentration of oxidative stress: oxidized LDL (U/l)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 5 and 8 weeks
Concentration of matrix metalloproteinases
Concentration of matrix metalloproteinases (MMPs, unit µM)
Time frame: 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.
Time frame: 1 and 19 weeks
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