Menopausal Hormone Therapy and Risk of Incident Hypertension

In This Article

Abstract and Introduction

Abstract

Objectives: Although menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor symptoms of menopause, its association with the development of arterial hypertension remains unclear. We sought to explore associations between different formulations of MHT and incident hypertension among menopausal women in a prospective cohort study.

Methods: We used the Etude Epidémiologique de femmes de la Mutuelle Générale de l'Education (E3N) cohort, a French prospective population-based study initiated in 1990 on 98,995 women. Out of these, 49,905 menopausal women with complete information on the use of MHT, and without prevalent hypertension at inclusion were included.

Results: The mean age of the population at baseline was 54.2±4.3 years, and 32,183 (64.5%) reported ever using MHT. Among these women, 10,173 cases of incident hypertension were identified over an average follow-up time of 10.6 years. Compared with women who never used MHT, those who ever used it had an increased risk of incident hypertension (adjusted HR 1.07, 95% CI 1.02–1.12) after adjustment for body mass index and other potential confounders. Oral but not transdermal estrogen use was associated with an increased risk of hypertension (adjusted HR=1.09; 95% CI: 1.04–1.14 and HR=1.03; 95% CI: 0.99–1.07, respectively). However, the HRs associated with oral and transdermal estrogens did not differ significantly (P-homogeneity=0.09). Regarding the role of concomitant progestogens, pregnane and norpregnane derivatives were significantly associated with hypertension risk (HR=1.12; 95% CI: 1.06–1.19 and HR=1.06; 95% CI: 1.01–1.13, respectively).

Conclusions: MHT was associated with a modest but significant increased risk of incident hypertension, especially when using oral estrogen in combination with a progestogen such as pregnane and norpregnane derivatives. Surveillance of blood pressure should be added to the medical surveillance of MHT users.

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Introduction

Although menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor symptoms of menopause, its association with the development of arterial hypertension remains unclear. Results from observational studies and clinical trials are inconsistent with respect to associations between MHT and blood pressure (BP).^[1–13] Associations with the development of hypertension may be different according to formulation and route of administration of estrogens.^[8,9,13]

We therefore sought to determine the associations between different formulations of MHT and incident hypertension among menopausal women in a large prospective cohort study.

Table 1. Baseline characteristics of 49,905 participants from the E3N cohort, by the use of menopausal hormone therapy during follow-up
Characteristics (%) or mean ± SD	Never use of menopausal hormone therapy n = 17,772	Ever use of menopausal hormone therapy n = 32,183
Age (y)	55.2 ± 4.7	53.6 ± 4.0
Body mass index (kg/m²)	22.3 ± 2.9	21.8 ± 2.4
Overweight (25≤BMI < 30 kg/m²)	15.6	10.8
Obesity (BMI≥30 kg/m²)	2.7	1.0
Smoking status
Current	30.9	34.0
Past	14.8	14.6
Never	54.3	51.4
Diabetes mellitus	0.14	0.07
Hypercholesterolemia	4.7	4.7
Physical activity (metabolic equivalents-h/wk)	45.4 ± 28.8	44.0 ± 27.0
Family history of hypertension	4.4	5.8
Education level
No high school	13.7	9.8
High school	50.7	51.6
University	35.6	38.6
Number of pregnancies	2.0 ± 1.2	2.0 ± 1.1
Hysterectomy	7.9	8.5
Age at menopause (y)	50.7 ± 4.0	50.2 ± 3.6
Surgical menopause^a	11.9	8.4

^aMenopause due to bilateral oophorectomy or to a specific medical condition (induced by radiation or a drug).

Table 2. Hazard ratios (HRs) and 95% confidence intervals (95% CI) for incident hypertension according to menopausal hormone therapy use
	Cases n = 10,173	Age-adjusted HR (95% CI)	Multivariable-adjusted HR^a (95% CI)
Use of menopausal hormone therapy
Never	3,649	Ref	Ref
Ever	6,524	1.01 (0.97–1.06)	1.07 (1.02–1.12)
Estrogen route of administration
Never	3,649	Ref	Ref
Oral	2,993	1.05 (1.00–1.10)	1.09 (1.04–1.14)^b
Transdermal	4,769	1.01 (0.96–1.05)	1.03 (0.99–1.07)
Other	1,517	0.99 (0.93–1.04)	0.99 (0.94–1.06)
Formulation of menopausal hormone therapy
Never	3,649	Ref	Ref
Estrogen alone	1,479	1.03 (0.98–1.09)	1.03 (0.97–1.09)
Estrogen with progestogen	5,589	0.99 (0.95–1.03)	1.05 (1.01–1.20)
Progesterone	1,927	0.96 (0.91–1.01)	0.97 (0.92–1.02)
Dydrogesterone	1,537	0.97 (0.92–1.03)	0.99 (0.94–1.05)
Pregnane derivatives	1,840	1.08 (1.03–1.14)	1.12 (1.06–1.19)^c
Norpegnane derivatives	2,035	1.02 (0.97–1.07)	1.06 (1.01–1.13)^d
Testosterone derivatives	711	1.03 (0.95–1.11)	1.06 (0.98–1.14)
Other	94	0.88 (0.71–1.07)	0.87 (0.71–1.06)
Weak estrogen ^e	676	1.02 (0.94–1.11)	1.06 (0.98–1.15)
Other estrogen	825	1.01 (0.94–1.08)	1.00 (0.93–1.08)

Bold values are for statistically significant results.
Models were stratified by years of birth and age was used as time-scale.
^aAdjusted for body mass index, hypercholesterolemia, diabetes, education level, smoking status, family history of hypertension, physical activity, age at menopause, type of menopause, age at menarche, number of pregnancies, and use of oral contraceptive.
^b P = 0.09 for comparison of oral estrogen versus transdermal estrogen; P = 0.02 for comparison of oral estrogen versus other route of administration.
^c P < 0.001 for comparison of progesterone versus pregnane derivatives; P = 0.02 for comparison of progesterone versus norpregnane derivatives.
^d P = 0.003 for comparison of dydrogesterone versus pregnane derivatives; P = 0.01 for comparison of dydrogesterone versus norpregnane derivatives.
^eWeak estrogen was promestriene or estriol.

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Menopausal Hormone Therapy and Risk of Incident Hypertension

Role of the Route of Estrogen Administration and Progestogens in the E3N Cohort

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