By Jeffrey T. Jensen, MD, Editor
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports that he is a consultant for and receives grant/research support from Bayer, Abbvie, ContraMed, and Merck; he receives grant/research support from Medicines 360, Agile, and Teva; and he is a consultant for MicroChips and Evofem.
SYNOPSIS: Among otherwise healthy midlife women, the presence of frequent hot flashes was associated with impaired endothelial function, a risk factor for cardiovascular disease.
SOURCE: Thurston RC, Chang Y, Barinas-Mitchell E, et al. Physiologically assessed hot flashes and endothelial function among midlife women. Menopause 2017; Apr 10. doi:10.1097/GME.0000000000000857. [Epub ahead of print].
Changes that develop during the perimenopausal transition and early menopause may influence the development of cardiovascular disease (CVD). Hot flashes represent a hallmark symptom of menopause, reported by more than two-thirds of women, with about one-third complaining of frequent or severe symptoms. Although hot flashes frequently motivate women to seek hormonal therapy, available research has not determined whether the presence of vasomotor symptoms influences health beyond their effect on quality of life. Thurston et al enrolled a cohort of 272 healthy, nonsmoking women between 40-60 years of age to investigate the association between hot flash severity and endothelial function. By design, they enrolled an equal number of “nonflashers” (subjects who reported no hot flashes in the last three months) and “flashers” (subjects with daily hot flashes and/or night sweats). Exclusion criteria included any use of hormonal therapy or other medications known to influence hot flash severity (e.g., selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, gabapentin) in the last three months, hysterectomy and/or bilateral oophorectomy, history of CVD, pheochromocytoma, or cancer. All participants underwent a baseline physical exam, a blood draw (fasting estradiol, glucose, C-reactive protein, interleukin-6, and lipids), and a carotid artery ultrasound. The investigators assessed ambulatory hot flashes by having subjects use an electronic hot flash diary and wrist actigraph to prospectively record the severity and frequency over three days (active) and a physiologic hot flash monitor that quantified hot flashes via sternal skin conductance over 24 hours (passive). In addition, the subjects also completed a questionnaire that assessed the frequency and bother of hot flashing over the two weeks prior to enrollment. The primary outcome was the association between hot flashes and endothelial function using brachial artery flow-mediated dilation (FMD), a well-validated and widely used index of endothelial function.1 A low FMD indicates poor endothelial function, a risk factor for CVD.
The mean age of participants was 54 years, with 50% reporting no hot flashes. As expected, the proportion of subjects reporting hot flashing increased with age, ranging from 38% in the group ≤ 53 years of age to 71% in the group > 56 years of age. Overall, participants reported an average of two hot flashes during waking hours, and the physiologic monitoring showed an average of six hot flashes per 24 hours.
For the entire study population, FMD did not differ between ‘‘flashers’’ (% mean [SE] = 7.37 [4.18]) and ‘‘nonflashers’’ (7.60 [3.91]). Furthermore, the frequency of physiologic or reported hot flashes also did not correlate with FMD. However, age significantly modified the association. “Flashers” aged 40-53 years (youngest tertile) had significantly lower FMD than “nonflashers,” and a greater frequency of physiologic hot flashes correlated with poorer FMD in these younger women. Of interest, estradiol levels did not reduce the magnitude or significance of the hot flash-age interactions with FMD. However, the median estradiol level across all age groups was 5 pg/mL (only 5.4 pg/mL in the 40- to 53-year age group). None of the other covariates measured at baseline explained the observed association of hot flashes and FMD in these younger subjects.
COMMENTARY
Whether early initiation of hormonal therapy can reduce the long-term risk of CVD remains controversial. The Estrogen in Prevention of Atherosclerosis Trial (EPAT) showed a reduction of atherosclerosis progression in postmenopausal women without coronary heart disease who were treated with oral estradiol.2 The Early versus Late Intervention Trial with Estradiol (ELITE) study found that initiation of oral estradiol and vaginal micronized progesterone within six years of onset of menopause reduced the progression of atherosclerosis, an effect not seen when therapy was initiated after 10 years.3
In this study, Thurston et al found that younger (≤ 53 years of age) women experiencing hot flashes had lower FMD than “nonflashers” of the same age, an effect not observed in older age cohorts. The development of atherosclerotic plaque occurs in the setting of elevated lipids, a pro-inflammatory environment, and endothelial damage. Estrogen receptor α and β are expressed in the endothelium, and estrogen signaling contributes to healthy endothelial function.4 Rossi et al conducted a prospective evaluation that validated the use of FMD as a marker of CVD in postmenopausal women. Compared to women in the highest tertile of FMD, the adjusted relative risk of an incident cardiovascular event for women in the lowest tertile was 4.42 (95% confidence interval, 2.97-8.01), and low FMD contributed significantly to the model predicting cardiovascular events.1 In a cross-sectional study, Moreau et al demonstrated a decline in FMD and endothelial function that begins during the perimenopause and then worsens with the loss of ovarian function and prolonged estrogen deficiency.
The important contribution of the Thurston et al study is the linkage of vasomotor symptoms to impaired FMD. While an independent effect of estradiol was not seen in this study, the median levels of estradiol were extremely low, suggesting well-established estrogen deficiency, even in the youngest age tertile. This may have made it difficult to observe an independent association. Regardless, the finding that younger women in the perimenopausal transition or early post-menopause who experience hot flashes are a group with impaired endothelial function strongly supports a recommendation for hormonal therapy as an intervention to prevent CVD. Keep in mind that the available literature suggests that estrogen replacement improves FMD and endothelial function in younger postmenopausal women, but the effect diminishes over time,5 findings consistent with the “timing hypothesis.” Clinicians treating perimenopausal women should inquire about the presence of hot flashes, and discuss hormone therapy in women with symptoms.
REFERENCES
- Rossi R, Nuzzo A, Origliani G, Modena MG. Prognostic role of flow-mediated dilation and cardiac risk factors in post-menopausal women. J Am Coll Cardiol 2008;51:997-1002.
- Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939-953.
- Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221-1231.
- Khalil RA. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease. Biochem Pharmacol 2013;86:1627-1642.
- Sherwood A, Bower JK, McFetridge-Durdle J, et al. Age moderates the short-term effects of transdermal 17beta-estradiol on endothelium-dependent vascular function in postmenopausal women. Arterioscler Thromb Vasc Biol 2007;27:1782-1787.
Among otherwise healthy midlife women, the presence of frequent hot flashes was associated with impaired endothelial function, a risk factor for cardiovascular disease.
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