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口服雌激素與無擾人熱潮紅症狀婦女出現令人不悅的血管效應有關
作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　October 1, 2009 — 根據10月Obstetrics Gynecology期刊中報告的隨機控制試驗結果，口服雌激素與沒有令人困擾之熱潮紅現象婦女出現令人不悅的血管效應有關。
　　
　　芬蘭赫爾辛基大學醫學中心的Pauliina Tuomikoski醫師等人寫道，停經後的荷爾蒙治療(HT)曾經被建議用於預防心血管疾病。此一建議是根據對於最近停經、特別是有血管收縮熱潮紅的婦女、決定開始使用HT的許多觀察研究，發現心血管疾病風險顯著降低(幾乎達40–60%)。不過，在隨機雙盲安慰劑控制試驗中，沒有血管收縮熱潮紅或者症狀輕微的年長婦女，HT對於心血管疾病預防的初級或次級終點沒有效益。
　　
　　研究目標是比較出現不能忍受之熱潮紅（定義是每天超過7次的中度到嚴重發作）的婦女和可忍受熱潮紅（定義是每天小於3次的輕微發作）的婦女，使用HT時的血管反應。研究對象包括143名健康、最近停經的婦女，其平均年紀為52.4 ± 0.2歲，停經之後的平均時間為19.5 ± 0.9個月。
　　
　　每一類的婦女被隨機指派接受1 mg的經皮雌二醇凝膠、口服雌二醇(2 mg)，併用或不併用每天給予的醋酸甲羥孕酮(medroxyprogesterone acetate)、或者安慰劑，為期6個月。使用脈波分析評估血管功能，使用硝基甘油(nitroglycerin)和沙丁胺醇(salbutamol)挑釁測試(challenges)來評估內皮功能。
　　
　　出現無法耐受的熱潮紅，並不影響各種類型HT治療的動脈或大動脈僵硬或內皮功能變化等反應。不過，在可耐受熱潮紅的病患中給予硝基甘油之後，使用雌二醇與發生第一次收縮尖峰(根據心室射出的快速期)的時間減少13.2%有關(P = .028)。給予硝基甘油之後，發生反射波的時間(根據脈波速率)也減少8.4%(P = .018)。無法忍受熱潮紅的婦女沒有出現這些反應，也沒有出現任何可耐受熱潮紅婦女使用其他治療處方時的任何反應。
　　
　　研究限制包括，無法一般化到肥胖婦女或者其他種族婦女，有關熱潮紅的次數與嚴重度使用的是主觀資料，使用期間只有6個月。
　　
　　研究作者寫道，沒有令人困擾之熱潮紅的婦女，在口服雌激素治療之後，可能會出現令人不悅的血管反應，導致較不好的血管構造。這可部份解釋HT相關心血管疾病效果之觀察研究和隨機臨床試驗的結果差異，因為在觀察研究中，婦女可能在開始使用HT時發生熱潮紅，而進入臨床試驗的婦女，並沒有令人困擾的熱潮紅。因此，在未來評估HT和心血管疾病的研究中，熱潮紅狀態應被視為一個可能的干擾因素。
　　
　　芬蘭停經研究協會、PAivikki與Sakari Sohlberg基金會、Emil Aaltonen基金會、Nylands Nation、Orion 研究基金會、芬蘭-挪威醫學基金會、芬蘭醫學基金會、赫爾辛基大學醫學中心研究基金等支持本研究。研究作者皆宣告沒有相關財務關係。
　　  

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.

Obstet Gynecol. 2009;114:777-785.