Influence of hormone therapy on the cardiovascular responses to stress of postmenopausal women

https://doi.org/10.1016/j.biopsycho.2004.11.004Get rights and content

Abstract

Epidemiological and psychophysiological data suggest that groups that differ in reproductive hormones and stress responses also differ in risk for cardiovascular disease. To evaluate the effects of hormone therapy on women's cardiovascular responses to laboratory stressors, 89 healthy postmenopausal women were tested twice, before and after exposure for about 8 weeks to one of the five conditions: placebo, Estratab (primarily estrone), Estratab plus Prometrium (micronized progesterone), Estratab plus Provera (synthetic progestin), and Estratest (same estrogen as in Estratab plus methyltestosterone). Results showed that women assigned to Estratab plus Prometrium and Estratest had diminished systolic blood pressure responses to stress upon retesting, whereas the other groups did not change in the level of their responses. Women assigned to Estratab plus Prometrium had diminished diastolic blood pressure responses during a speech stressor upon retesting, whereas women assigned to Estratab plus Provera increased. Our findings show that hormone therapy does affect women's stress responses, but they do not provide a simple explanation as to why groups at high and low risk for cardiovascular disease differ in reproductive hormones and stress responses.

Introduction

Frequent and large cardiovascular responses to psychosocial stress are posited to be a marker of or risk factor for progression of atherosclerosis (Matthew et al., 1986, Treiber et al., 2003). Available prospective data demonstrate an association between the magnitude of cardiovascular responses to stress, termed cardiovascular reactivity, and carotid atherosclerosis in men and women (Barnett et al., 1997, Everson et al., 1997, Lynch et al., 1998, Matthews et al., 1998b) and coronary atherosclerosis in a cynamolgus monkey model (Manuck et al., 1989). Other relevant findings are prospective associations between blood pressure reactivity and the development of hypertension, a risk factor for atherosclerosis (Matthews et al., 2004, Treiber et al., 2003).

Groups that differ in reproductive hormone status differ in the magnitude of their cardiovascular responses to psychosocial stress as well as their risk for atherosclerosis. Men are at higher risk for coronary heart disease (CHD) than are premenopausal women and have elevated blood pressure and neuroendocrine responses to laboratory stressors (Matthews and Stoney, 1988, Stoney et al., 1987). Furthermore, men have greater total peripheral resistance responses, whereas women have greater cardiac output responses (Allen and Matthews, 1997, Girdler et al., 1990). Postmenopausal women are at higher risk for CHD than are premenopausal women, although statistical controls for risk factors and age reduce the association substantially (Colditz et al., 1987, Gordon et al., 1978). Postmenopausal women have elevated cardiovascular and neuroendocrine responses to stress relative to premenopausal women, especially to an interpersonal stressor (Blumenthal et al., 1991, Owens et al., 1993, Saab et al., 1989). Pregnant women exhibit decreases in stress-induced diastolic blood pressure responses compared to their prepregnancy levels or to matched nonpregnant controls (Matthews and Rodin, 1992). Women who undergo bilateral oophorectomy or ovariectomized cynamologus monkeys are at elevated risk for CHD or extensive atherosclerosis (Adams et al., 1985). Women who undergo bilateral salpingo oophorectomy tend to show larger increases in blood pressure responses to stress after surgery relative to those exhibited by women who underwent hysterectomy with ovarian conservation (Stoney et al., 1997). Taken together, these findings support the possibility the reproductive hormones influence cardiovascular responses to stress, which, in turn, affect CHD risk.

One approach to test this possibility is to compare the stress responses of postmenopausal women using estrogen therapy with those who do not or who are on placebo. Table 1 describes studies that compare women using various hormone preparations, usually estrogen therapy. Two randomized trials exposed women to 1 day of high dose transdermal estrogen and reported declines in blood pressure reactivity, with one study also showing a decline in epinephrine reactivity (Del Rio et al., 1998, Manlem et al., 2002). Of the 11 randomized trials exposing women to more standard duration and types of regimens, three reported lowering of blood pressure or vascular resistance during stress with estrogen therapy as compared to placebo (Ceresini et al., 2000, Komesaroff et al., 1999, Lindheim et al., 1992, Lindheim et al., 1994) and two reported the reduced blood pressure response in subgroups (nonsmokers in Girdler et al. (2000); diabetics in Manwaring et al. (2002); c.f. McCubbin et al. (2002)). In contrast, three reports using overlapping participants found a lowering of blood pressure with estrogen that was not specific to stress (Girdler et al., 2004, Light et al., 2001, West et al., 2001) and several reported no differences between estrogen therapy and placebo conditions in blood pressure or vascular reactivity (Farag et al., 2002, Matthews et al., 2001; c.f. Komesaroff et al., 1999; Matthews et al., 1998a). Taken together, these findings suggest that estrogen might have a beneficial impact on blood pressure regulation, but its effect may not be unique to stress responses. This hypothesis is consistent with data showing that estrogen stimulates release of nitric oxide from the endothelium, which, in turn, leads to vasodilation (Schwertz and Penckofer, 2001, Virdis et al., 2000) and that postmenopausal women using hormone therapy have greater brachial artery flow-mediated dilation than postmenopausal women not using hormone therapy (Bush et al., 1998, McCrohon et al., 1996; c.f. Girdler et al., 2004).

Estrogen is not the only reproductive hormone that differs by sex, menopausal status, or pregnancy status. Perhaps the effects of estrogens on cardiovascular responses to stress are modified by their interaction with progesterone and androgens, which also differ by these groups. Some data suggest that progesterone, a specific steroid made by the placenta and corpus luteum, and progestins, synthetic molecules that have progestational effects, may attenuate the beneficial effects of estrogens on cardiovascular risk factors. For example, in the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI, 1995), postmenopausal women randomized to Premarin (i.e., conjugated equine estrogens), plus Provera, a progestin (specifically, medroxyprogesterone acetate or MPA), had lower high-density lipoprotein cholesterol and higher total cholesterol than women randomized to placebo, Premarin alone, or Premarin plus micronized progesterone. Two hour fasting glucose levels were also elevated in the Provera group.

The influence of progestins has been tested in several randomized studies (see Table 1). Several suggest that adding MPA attenuates the beneficial effect of estrogen therapy on blood pressure responses to stress (Lindheim et al., 1994, Manwaring et al., 2002), but two studies show no differences between those on MPA versus not (Light et al., 2001, West et al., 2001) and one study showed a favorable lowering of resistance and increase in cardiac output during stress with the addition of Provera, relative to estradiol alone or placebo (Farag et al., 2002). To our knowledge, no study has evaluated the effects of progesterone (as opposed to progestin) therapy on stress responses.

Androgens added to estrogen lead to a reduction in sex hormone binding globulin, thereby increasing the bioavailability of endogenous and exogenous androgens (Simon et al., 1999). There are no studies of the influence of the addition of androgen to estrogen therapy on stress responses, which is of interest, given sex differences in androgen exposure and the relative differences in exposure in postmenopausal women. Studies indirectly relevant to the role of androgens have examined the stress responses of women with central adiposity, which is associated with high androgen levels and increased risk of coronary disease (Despres et al., 1990). Women with central adiposity show elevated blood pressure and vascular resistance responses to stress (Davis et al., 1999, Waldstein et al., 1999), with a mediating role thought to be related to hyperinsulinemia. On the other hand, some data suggest that androgen actions on the arterial wall appear to support the vasodilator and antiatherosclerotic effects of estrogens (Adams et al., 1995, Sarrel and Witta, 1997). Perhaps these latter beneficial effects are apparent only in the presence of normal levels of insulin.

The purpose of the present study was to evaluate the effects of four different hormone regimens compared to placebo on cardiovascular responses to psychological stressors of healthy postmenopausal women. Placebo and estrogen alone (Estratab, primarily estrone) conditions were included for comparison with conditions of estrogen plus the following: continuous Provera, micronized progesterone (Prometrium), and testosterone (Estratest). Women were randomized to these five conditions and tested on two occasions, one prior to randomization and one after 8 weeks of treatment. Their menopausal-related quality of life was measured to determine whether any obtained stress effects might be due to or accompanied by changes in physical or psychological function (c.f. Hammarback et al., 1985, Sarrel, 1999). We anticipated that estrogen alone would have the most favorable effect on stress-induced changes in blood pressure and vascular function, i.e. lead to a smaller response to stress after treatment, and that the addition of Provera would lessen the beneficial effect of estrogen.

Section snippets

Subjects

Participants were 97 women between the ages of 48 and 65 recruited through local advertisements. Exclusion criteria were body weight >30% than ideal body weight as determined by Metropolitan Life Tables; history of medication-dependent diabetes, heart disease, pulmonary embolism or deep vein thrombosis, liver or pancreatic disease, and hypertension; use of lipid lowering drugs, and daily use of steroids, current use of medications that would affect cardiovascular function; and unwillingness to

Demographic and anthropometric characteristics

The characteristics of the entire sample at the first laboratory session are shown in Table 2. There were no significant group differences in age, years of education, race, marital status, highest educational degree attained, current occupational status, family income, or family history of high blood pressure, diabetes, angina, myocardial infarction, other heart disease, stroke or cancer. Eight women were smokers and 1–3 smokers were in each group. There were no group differences in baseline

Discussion

The overarching aim of our work has been to understand why groups that differ in reproductive hormone levels also differ in the magnitude of their cardiovascular and neuroendocrine responses to stress. We initially focused on conducting naturalistic experiments by examining changes in stress responses during and after pregnancy (Matthews and Rodin, 1992), and before and after hysterectomy/bilateral oophorectomy (Stoney et al., 1997), to evaluate the possible role of changes in reproductive

Acknowledgements

This paper was supported by HL38712, HL65111, HL65112, and Solvay Pharmaceuticals (Marietta, Georgia). We thank Leslie Mitrik, Karen Kenyon, and Sonya Brady for their invaluable assistance on the project and Peter Gianaros for his valuable comments on an earlier version of the manuscript.

References (60)

  • G. Rosano et al.

    Natural progesterone, not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women

    J. Am. Coll. Cardiol.

    (2000)
  • M. Stampfer et al.

    Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence

    Prev. Med.

    (1991)
  • S.G. West et al.

    Transdermal estrogen reduces vascular resistance and serum cholesterol in postmenopausal women

    Am. J. Obstet. Gynecol.

    (2001)
  • M.R. Adams et al.

    Ovariectomy, social status, and atherosclerosis in cynomolgus monkeys

    Arteriosclerosis

    (1985)
  • M.R. Adams et al.

    Effects of androgens on coronary atherosclerosis and atherosclerosis-related impairment of vascular responsiveness

    Arterioscl. Thromb. Vasc. Biol.

    (1995)
  • M.T. Allen et al.

    Hemodynamic responses to laboratory stressors in children and adolescents: the influence of age, race, and gender

    Psychophysiology

    (1997)
  • P.A. Barnett et al.

    Psychological stress and the progression of carotid artery disease

    J. Hypertens.

    (1997)
  • D.A. Bellinger et al.

    Oral contraceptives and hormone replacement therapy do not increase the incident of arterial thrombosis in a nonhuman primate model

    Arterioscl. Thromb. Vasc. Biol.

    (1998)
  • J.A. Blumenthal et al.

    Stress reactivity and exercise training in premenopausal and postmenopausal women

    Health Psychol.

    (1991)
  • M.H. Burleson et al.

    Postmenopausal hormone replacement: effects on autonomic, neuroendocrine, and immune reactivity to brief psychological stressors

    Psychosom. Med.

    (1998)
  • G.A. Colditz et al.

    Menopause and the risk of coronary heart disease in women

    New Engl. J. Med.

    (1987)
  • M.C. Davis et al.

    Body fat distribution and hemodynamic stress responses in premenopausal obese women: a preliminary study

    Health Psychol.

    (1999)
  • G. Del Rio et al.

    Acute estradiol and progesterone administration reduced cardiovascular and catecholamine responses to mental stress in menopausal women

    Neuroendocrinology

    (1998)
  • J. Despres et al.

    Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease

    Arteriosclerosis

    (1990)
  • S.A. Everson et al.

    Interaction of workplace demands and cardiovascular reactivity in progression of carotid atherosclerosis: population based study

    Br. Med. J.

    (1997)
  • S.S. Girdler et al.

    Transdermal versus oral estrogen therapy in postmenopausal smokers: hemodynamic and endothelial effects

    Obstet. Gynecol.

    (2004)
  • S.S. Girdler et al.

    Gender differences in blood pressure control during a variety of behavioral stressors

    Psychosom. Med.

    (1990)
  • T. Gordon et al.

    Menopause and coronary heart disease: the Framingham study

    Ann. Intern. Med.

    (1978)
  • S. Hammarback et al.

    Cyclical mood changes as in the premenstrual tension syndrome during sequential estrogen–progestogen postmenopausal replacement therapy

    Acta Obstet. Gynecol. Scand.

    (1985)
  • S. Hulley et al.

    Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women

    JAMA

    (1998)
  • Cited by (13)

    • Hormonal and nonhormonal treatment of vasomotor symptoms

      2015, Obstetrics and Gynecology Clinics of North America
      Citation Excerpt :

      Testosterone (Androderm, Testim) has not shown any benefit in the treatment of vasomotor symptoms. It has potential adverse effects, including negative effects on the lipid parameters, clitoromegaly, hirsutism, and acne.32 Testosterone is not recommended for the treatment of hot flashes.

    • The effects of exogenous progesterone on drug craving and stress arousal in cocaine dependence: Impact of gender and cue type

      2013, Psychoneuroendocrinology
      Citation Excerpt :

      Significant reductions in SBP following stress and cue relative to the relaxing condition was also observed in females administered progesterone, but not observed in the other groups. Findings support a study assessing the effects of gonadal hormones on cardiovascular response to stress in menopausal women, where the combined administration of Estratab (esterone) plus Prometrium (micronized progesterone) significantly lowered blood pressure following a speech stressor (Matthews et al., 2005). Findings also tentatively corroborate studies that have shown micronized progesterone to provide beneficial effects on ambulatory blood pressure in menopausal women (Lee et al., 2011).

    • Menopausal hormone therapy and cardiovascular disease

      2006, Revista Espanola de Cardiologia
    • Pharmacological therapy for vasomotor symptoms in breast cancer survivors

      2017, Essentials of Menopause Management: A Case-Based Approach
    View all citing articles on Scopus
    View full text