Oral Estrogen Linked to Unfavorable Vascular Effects in Women Without Troublesome Hot Flushes
By Laurie Barclay, MD
Medscape Medical News
October 1, 2009 — Oral estrogen is linked to unfavorable vascular effects in women without troublesome hot flushes, according to the results of a randomized controlled trial reported in the October issue of Obstetrics Gynecology.
"Postmenopausal hormone therapy (HT) was once recommended for the prevention of cardiovascular disease," write Pauliina Tuomikoski, MD, from Helsinki University Central Hospital in Helsinki, Finland, and colleagues. "This recommendation was based on the marked reduction (approximately 40–60%) of cardiovascular disease risk in the numerous observational studies when recently postmenopausal women, typically with severe vasomotor hot flushes, had decided to initiate HT. However, when older women with no or minimal vasomotor hot flushes were treated in randomized, double-blind, placebo-controlled trials, HT had no beneficial effect in secondary or primary prevention of cardiovascular disease."
The goal of this study was to compare the vascular responses to HT in women with intolerable hot flushes, defined as more than 7 moderate to severe episodes per day, vs women with tolerable hot flushes, defined as fewer than 3 mild episodes per day. The study sample consisted of 143 healthy, recently postmenopausal women, mean age 52.4 ± 0.2 years, and mean time since menopause, 19.5 ± 0.9 months.
Women in each category were randomly assigned to receive 1 mg of transdermal estradiol gel, oral estradiol (2 mg) with and without daily medroxyprogesterone acetate, or placebo for 6 months. Pulse wave analysis was used to evaluate vascular function, and endothelial function was assessed with nitroglycerin and salbutamol challenges.
The presence of intolerable hot flushes did not affect the changes in arterial or aortic stiffness or endothelial function seen in response to various forms of HT. In participants with tolerable hot flushes, however, use of oral estradiol was associated with a 13.2% decrease (P = .028) in time to the first systolic peak (dependent on the rapid phase of ventricular ejection) after nitroglycerin. There was also a decrease of 8.4% in time to the reflected wave (dependent on pulse wave velocity) after nitroglycerin (P = .018). Women with intolerable hot flushes did not show these effects, nor were any effects noted with other treatment regimens in women with tolerable hot flushes.
Limitations of this study include lack of generalizability to obese women or to women of other ethnic origins, subjective data regarding the number and severity of hot flushes, and exposure time of only 6 months.
"Women without troublesome hot flushes are susceptible to unfavorable vascular effects after oral estrogen treatment, resulting in less compliant vasculature," the study authors write. "This could partly explain the divergent results between observational studies and randomized clinical trials in which HT-related cardiovascular disease effects have been assessed, since in observational studies, women were likely to have experienced hot flushes when initiating HT, whereas women entering clinical trials did not have troublesome hot flushes. Thus, in future studies assessing HT and cardiovascular disease endpoints, hot flush status should be considered as a potential confounding factor."
The Finnish Society for Menopause Research, the Paivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Nylands Nation, the Orion Research Foundation, the Finnish-Norwegian Medical Foundation, the Finnish Medical Foundation, and the Helsinki University Central Hospital Research Fund supported this study. The study authors have disclosed no relevant financial relationships.
