Estrogen Supplementation in Perimenopausal Women

Abstract & Commentary

Synopsis: Estrogen supplementation of hypoestrogenic perimenopausal women attenuated blood pressure, cortisol, and catecholamine responses to acute psychological challenge.

Source: Komesaroff PA, et al. J Clin Endocrinol Metab 1999;84:606-610.

The present study tested the hypothesis that estradiol reduces cortisol and catecholamine responses to stress. Twelve women within two years of their last menses with hot flashes were designated as being perimenopausal. Women with known cardiovascular disease, including hypertension, were excluded. These women were then randomized to 12 weeks of estradiol valerate, 2 mg daily by mouth, or placebo. Outcome variables that were determined before and after estradiol use included cortisol, adrenocorticotropic hormone (ACTH), epinephrine, norepinephrine, blood pressure, and heart rate. Estradiol levels rose from about 35 pg/mL to 250 pg/mL, which is well above physiological levels. After estradiol supplementation, the increases in both systolic and diastolic blood pressure in response to mental stress were reduced, and cortisol, ACTH, epinephrine, and norepinephrine responses were attenuated.

Comment by sarah l. berga, md

There are several mechanisms by which estrogen protects against cardiovascular disease. One of these is thought to be reduced endocrine and vascular reactivity to psychological challenge. Indeed, estrogen exerts direct effects upon the vessel wall and vasomotor tone. Previous studies by Komesaroff and colleagues found that estrogen supplementation of perimenopausal women enhanced basal nitric oxide release from the vessel wall and reduced norepinephrine-induced vasoconstriction. In the present model, Komesaroff et al extend their previous work by asking whether estrogen supplementation alters cardiovascular and endocrine responses to psychological challenge.

The use of a challenge paradigm has advantages over studies in which a given vasoconstrictor agent is directly infused. Multiple factors regulate vasomotor tone and cardiovascular reactivity, and psychological challenge is thought to activate all or many of these mechanisms, including cortisol and catecholamine release. Further, basal endocrine and cardiovascular parameters do not adequately reflect what happens when an individual is confronted by the mundane trials of daily living. Therefore, to better approximate what happens in response to minor stress, Komesaroff et al used a psychological challenge, performing difficult arithmetic tasks in a distracting milieu.

Komesaroff et al found that estrogen administration reduced cardiovascular and endocrine reactivity. They suggested a direct link between reduced adrenal secretion and reduced blood pressure during challenge. While their discussion focused on the implications of reduced endocrine reactivity for cardiovascular risk, reduced cortisol and catecholamine secretion in response to mundane challenges could have other benefits as well. Another likely benefit of reduced endocrine reactivity is a lower risk of depression and dementia. Bone health is reduced by chronic glucocorticoid elevations, even when the glucocorticoid exposure is from an endogenous source. Chronic adrenal activation leads to reproductive compromise and hypothalamic hypothyroidism. Animal tests suggest that sustained increases in endocrine reactivity accelerate the aging process in general, possibly by increasing programmed cell death (apoptosis). Obviously, it is impossible to rid ones life of stress, so the prudent course is to take measures to reduce ones endocrine and cardiovascular reactivity to such pressures. While many of the ways to reduce mental stress involve psychological mechanisms such as "attitude readjustment" (in hypogonadal women at least), one should ensure that estrogen levels are adequate.

This study nicely demonstrates the profound effect of estrogen administration upon cardiovascular and endocrine reactivity, but, like all good studies, it raises certain questions. As Komesaroff et al point out, the effect of progestins in this model have not been determined. Perhaps more important, the effect of phyto- estrogens, tamoxifen, or raloxifene upon these parameters should be studied. Many women have chosen these and other estrogen alternatives in the belief that their use would confer the benefits of estrogen while reducing the risk of breast cancer. Given that we are still engaged in specifying the multiple mechanisms underlying the benefits (and risks) of postmenopausal estrogen use, it is impossible to know what to expect from the long-term use of estrogen alternatives. However, the development of investigative paradigms, such as the one in this study, may well allow for informative comparisons that are less labor- and time-intensive than long-term, large-scale epidemiological trials.