Effect of hormone therapy on blood pressure in postmenopausal women with mild hypertension

Status : Approved
First Submitted Date : 2020/09/06     Registered Date : 2020/09/22     Last Updated Date : 2020/09/06    

Cardiovascular disease (CVD) including coronary heart disease (CHD) and stroke is the number 1 cause of death among women worldwide and hypertension belongs to the group of major risk factors of CVD with the strongest evidence for causation. Based on office blood pressure (BP), hypertension is defined as a systolic BP (SBP) of 140 mmHg or higher and/or diastolic BP (DBP) of 90 mmHg or higher. In the case of grade 1 hypertension with a low risk of CVD, lifestyle modifications including dietary alterations may be sufficient to delay or prevent the need for pharmacological intervention.
 Ambulatory BP monitoring (ABPM) can identify white-coat and masked hypertension, provides night-time readings, and is a stronger predictor of all-cause and cardiovascular mortality when compared with clinic BP. The loss of arterial elasticity leads to an increase in SBP and a decrease in DBP. Thus, arterial stiffness can precede hypertension and, importantly, be reversible in conjunction with lifestyle change or anti-hypertensive treatment.
 A sex difference in the prevalence of hypertension is apparent: such is lower in women aged 20 to 34 years than in men but increases steeply after menopause, leading to a cross-over after the age of 70 years. Further, the role of hypertension in death is greater in women than in men. These statistics strongly suggest a key role of ovarian hormones in hypertension. If initiated in early menopause, menopausal hormone therapy (MHT) using oral estrogen decreases the risk for CHD but has no impact on stroke. The effects of estrogen therapy on BP may differ by the route of administration probably via a first-pass hepatic effect. Conjugated equine estrogen (CEE), an oral estrogen, increases the clinic BP, whereas parenteral estrogen using a transdermal patch decreases ambulatory BP in postmenopausal women with both hypertension and normal BP. When compared with patch application, percutaneous estradiol gel (PEG), another parenteral preparation, has lower adverse skin effects and could provide higher estradiol serum values with less day-to-day variation. Medroxyprogesterone acetate (MPA) prescription is on the steep decline these days because of adverse impacts on estrogen in CHD and breast cancer. Thus, the search for a safe and effective progestogen for MHT is one of the top-priority matters in the field of menopause. The effects of progestogen on BP have been less well studied to date. Our group previously reported that micronized progesterone (MP4), combined with CEE, exerted favorable impacts on ambulatory BP in a prospective study.
 The purpose of this study was to evaluate the impact of MP4 added to PEG on ambulatory BP and arterial stiffness in postmenopausal Korean women with grade 1 hypertension.

Treatment

1. Drug
 1) Estrogen: 17β-estradiol 1 mg (2 pumps)/day, 0.1% percutaneous gel (Estreva gel, Samil Pharm. Co., Seoul, Korea)
 2) Progestogne: micronized progesterone 100 mg(1 capsule)/day, per os (Utrogestan, Besins Healthcare, Brussel, Belgium)
2. Intervention arm
 1) Placebo
 2) Estrrogen therapy
 3) Estrrogen + progestogen therapy

Estrogen, placebo; 2 pumps/day
Progestogen. placebo; 1 capsule/day

Estrogen, active; 2 pumps/day
Progestogen, placebo; 1 capsule/day

Estrogen, active; 2 pumps/day
Progestogen, active; 1 capsule/day

Postmenopausal women (duration of amenorrhea:  12 months or longer or serum follicle-stimulating hormone value: 30 mIU/mL or higher) 
Grade 1 hypertension: according to clinic BP measured at the arm, systolic BP of 140 to 159 mmHg or diastolic BP of 90 to 99 mmHg. 
Women with uncontrolled hypertension using antihypertensive medication for at least six months 
Women whose BP was controlled but who wanted to hold their BP medication were included if the BP rebounded only to grade 1 after two weeks of washout.

Symptomatic coronary heart disease or stroke 
Current or recent (within one year prior to enrollment) smoking 
Uncontrolled diabetes mellitus (glycated hemoglobin > 8%)
Secondary hypertension
Hypertension with serious target organ injury suspected
Current or recent (within three months before the time of the study entry) MHT use
Contraindications for MHT including acutely impaired liver function, breast cancer, and venous thrombosis.

Ambulatory blood pressure

after 12-week treatment

Arterial stiffness

after 12-week treatment