A double-blind, placebo controlled study of postmenopausal oestrogen replacement therapy and carotid artery pulsatility index
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1 British Journal of Obstetrics and Gynaecology April 1998, Vol. 105, pp A double-blind, placebo controlled study of postmenopausal oestrogen replacement therapy and carotid artery pulsatility index Simon Jackson Senior Registrar, Sanjay Vyas Consultant Department of Obstetrics and Gynaecology, Southmead Hospital, Bristol Objective To determine whether postmenopausal oestrogen replacement therapy affects carotid artery pulsatility index. Design A prospective double-blind placebo controlled trial. Setting University associated teaching hospital. Participants Twenty-eight postmenopausal women who were more than 12 months postmenopausal and who had not taken exogenous oestrogen. Interventions Independent randomisation to receive oral oestradiol(2 mg daily) or placebo for 20 to 24 weeks. Main outcome measures Internal carotid artery Doppler pulsatility index, measured within one centimetre of the carotid bifurcation. Results Replicate data were available from 27 women. The mean pulsatility index decreased by in 15 women receiving oestradiol, compared with a mean rise of 0.05 in the 12 women who received placebo (P = 0-006,95% CI for treatment difference ). Conclusions Oestrogen replacement decreases postmenopausal carotid artery pulsatility index, probably reflecting decreased peripheral vascular resistance. This is a further mechanism whereby hormone replacement therapy may impart cardiovascular protection. INTRODUCTION Cardiovascular disease is the leading cause of mortality among women, exceeding deaths from all malignancies in women older than 60 years of age. The incidence of arterial disease increases substantially in the postmenopausal period, and it is possible that the hypo-oestrogenic state contributes to this. Epidemiological data suggest that the use of postmenopausal oestrogen protects against arterial disease, with a reduction in the incidence of ischaemic heart disease2 and cerebrovascular disease. Paganini-Hill et al.3 reported that the incidence of stroke decreased among oestrogen users in an elderly retirement community with a median age of 73 years in California (RR 053, 95% CI ). Falkeborn et al4 found that women older than 60 years had a significant reduction in the incidence of stroke if they used oestrogens, although such an effect was not observed for women up to 59 years. Furthermore, in women taking hormone replacement therapy (HRT) there may be a decreased risk ofalzheimer s disease5f. Correspondence: Mr S. R. Jackson, Department of Obstetrics and Gynaecology, Southmead Hospital, Bristol BSlO 5 NB, UK. Postmenopausal oral oestrogen replacement therapy is associated with reduced low density lipoprotein (LDL) and increased high density lipoprotein (HDL), but it has been estimated that this would only account for about 30% of the observed reduction in cardiovascular risk*. A double blind, placebo controlled, cross-over study has reported that sublingual oestradiol, given 40 minutes before exercise, increases exercise time and delays ECG ST wave depression in women with known ischaemic heart diseaseg. The time scale of such an effect precludes a lipid-mediated mechanism; oestrogen appears to have other mechanisms of action. In vivo studies have reported that oestrogen dilates rabbit coronary arteries O and rat aorta and increased cerebral blood flow has been reported after oestrogen administration in Alzheimer s disease12 and during a migraine attacki3. Pulsed Doppler ultrasound and colour flow imaging provides a noninvasive method of investigating the arterial tree. Vessels can be identified and the pulsatility index measured, probably representing blood flow impedance downstream to the point of sampling and consequently giving a measure of arteriolar tone. Using this technique, oestrogen administration has been RCOG 1998 British Journal of Obstetrics and Gynaecology
2 HRT AND CAROTID ARTERY PULSATILITY INDEX 409 reported to reduce postmenopausal internal carotid and uterine pulsatility inde~ ~. ~, although the latter finding may have occurred secondary to increased endometrial thickness and vascularity rather than reduced arteriolar tone. These studies suggest that oestradiol has a direct vasodilating action; it has been postulated that oestradiol may exhibit calcium channel blocking properties 6 via oestradiol receptors present within the muscularis of human arteries. However, the hypothesis remains unproven and there is, as yet, no conclusive evidence that oestrogen exhibits vasodilatory properties in in vivo human tissue. Studies examining arterial pulsatility indices have been small and uncontrolled. We have undertaken a double-blind, placebo controlled trial to examine the effect of oral oestradiol on internal carotid artery pulsatility index. METHODS Women who were more than 12 months postmenopausal and had not taken exogenous oestrogen in the past 12 months were identified from a hospital outpatient clinic. They were informed of the aims of the study; ethical approval for the study was obtained from Southmead Hospital Ethics Committee, and informed consent was obtained. Where doubt existed about menopausal status in women who had had a hysterectomy, biochemical confirmation was sought by measurement of oestradiol concentrations (postmenopausal threshold < 100 pmovl). Contraindications included a history of cancer of the endometrium, liver or breast. Prior to treatment, all women who had not had a hysterectomy had a transvaginal pelvic ultrasound scan performed using a 7.5 Mhz, probe and were excluded from the trial if the endometrium was more than 4 mm thick. Women were randomised independently by the hospital pharmacy to receive oral oestradiol (2 mg one daily; Progynova, Schering Health, West Sussex, UK) or placebo; the women and the investigators both being unaware which treatment was given. Opposed treatment with progestogen was not given over the 20 to 24 week period to maintain the blind nature of the trial. However, if breakthrough bleeding occurred, the woman was investigated with a repeat transvaginal ultrasound scan. An endometrial biopsy, using a Pipelle de Cornier sampler, was performed if the endometrial thickness was > 6 mm, and opposed therapy with norethisterone (5 mg once daily for 12 days per month) was then started. Compliance was checked by counting the number of tablets not used and measuring serum oestradiol levels. Because women given active treatment had received unopposed oestrogen for up to 24 weeks, repeat transvaginal scanning was undertaken after completing the study and pipelle endometrial biopsy was performed if the endometrium exceeded 6 mm, to exclude endometrial hyperplasia or malignancy. Norethisterone (5 mg twice daily) for 12 days was subsequently prescribed for all women treated with oestradiol who had not had a hysterectomy performed. Doppler studies were scheduled at fourt to six weekly intervals, the final measurement occurring at 20 to 24 weeks. They were undertaken using a colour flow imaging system (Ultramark HDI, Bothell, Washington, USA) with a 5 Mhz linear transducer. All replicate studies were performed at the same time of day, in the same sound-proofed, semi-darkened room kept at a constant temperature. After the women had rested in a supine position for 5 minutes, the common carotid artery, carotid bulb and proximal internal and external carotid artery were idenitified by real time ultrasound. The internal carotid artery was identified and the pulsed Doppler range gate was placed across it within one centimetre of the bification. When at least three consecutive waveforms (representing three cardiac cycles) of adequate quality were obtained, the pulsatility index was calculated using spectrum analysis, where end-diastolic Doppler shift frequency is subtracted from peakdiastolic shift frequency and divided by the mean frequency shift over the cardiac cycle18. The higher the value, the greater the impedance to blood flow. The mean pulsatility index of three waveforms was recorded and the mean value of the pulsatility index from the right and left internal carotid was used in subsequent analysis. Statistical analysis No attempt was made to estimate the sample size required to show a significant difference in the pulsatility index before undertaking this study; such a power calculation is difficult to perform as normal ranges for carotid pulsatility index in postmenopausal women are not readily available. Therefore this should be regarded as a pilot study; a nonsignificant result would lead to a larger trial. We tested the null hypothesis that change in pulsatility index will not differ between the oestradiol and placebo treated groups over the 20 to 24 weeks of the study by comparing the change in pulsatility index for both cohorts using analysis of covariance, baseline pulsatility index being used as the covariate. RESULTS Twenty-eight women consented to participate in the study and independent randomisation by the pharmacy resulted in 16 women receiving oestradiol valerate and 12 placebo (Table 1). No eligible women were excluded from the trial but one woman receiving oestrogen dropped out of the trial
3 ~ ~ 410 s. JACKSON & s. VYAS Table 1. Demographic data on the 28 women recruited to the study. Values are given as median (range) or number. Oestrogen (n = 16) Placebo (n = 12) Age (years) 61 (51-71) 63 (49-73) Time since menopause (years)* 11 (1-28) 12 (2-19) No. having hysterectomy 4 4 *Data not available for three women who had a premenopausal hysterectomy with ovarian conservation. after three months to undergo elective surgery. Five of the women who had not had a hysterectomy suffered from breakthrough bleeding with oestradiol, 4 to 18 weeks after starting their treatment. These women were no longer 'double-blind' and subsequently received monthly progestogen therapy; none of these women had their carotid assessment during the progestogen phase of their cycle. Replicate data were therefore available from 27 women, 22 of whom remained double-blind throughout the study (Table 2). No cases of endometrial atypia were diagnosed. Pretreatment median serum oestradiol was 61 pmovl (range < pmol); post-treatment was 2 16 pmol/ L (range pmoll) with oestradiol. All oestradiol treated patients exhibited a rise in serum oestradiol after treatment, ranging between twofold and eightfold, and tablet returns indicated compliance in every case. The pre-treatment mean pulsatility index for the oestrogen-treated and placebo-treated groups was 1 a08 and 1.10, respectively. Mean pulsatility index decreased by in the 15 women receiving oestradiol, compared with a mean rise of 0-05 in the 12 receiving placebo (P = 0.006, 95% CI for treatment difference 0.06 to 0.31). If the five unblinded women receiving progesterone were excluded from the analysis, mean pulsatility index dropped by after oestrogen therapy (P = 0.017, 95% CI for the treatment difference 0.04 to 0.3 1). DISCUSSION Conducting a placebo controlled hormone replacement study of any duration on women who have not had a hysterectomy presents problems. Withdrawal bleeding associated with conventional cyclical combined therapy immediately unblinds the study and unopposed oestrogen was therefore administered. Prolonged treatment with unopposed oestrogen leads to cystic hyperpla~ia'~ and increases the risk of endometrial cancet2-21. Recent meta-analy~es~~,~~ show that while unopposed oestrogen increases the relative risk of endometrial carcinoma 2.3- fold and with prolonged therapy of more than 10 years 9.5-fold, the risk associated with oestrogen use for six Table 2. Change in pulsatility index (PI) during the study. Initial PI Oestrogen Placebo Final PI Change in PI Initial PI Final PI Change in PI I * Dropout I o* * I.oo 0.09* * *Progesterone given in addition to oestradiol. months or less is negligible (0-6-1 e4-fold). Ethical approval was therefore granted for a six month study, provided that endometrial surveillance was undertaken before and after the study. An endometrial thickness of - < 4-5 mm on transvaginal ultrasound has been found to be diagnostic of endometrial atrophy while significant endometrial pathology may exist above 6 mm24. Endometrial screening was therefore undertaken with ultrasound complimented by endometrial biopsy, if appropriate. Although we had initially planned to examine women in both groups at intervals of four to six weeks, this proved impractical in some cases. The women had been enrolled from a wide geographical area and some were elderly, making frequent hospital visits too arduous. However, we had stressed the importance of the (week 20-24) final visit, and all women in both groups attended for this investigation. Because of the paucity of the interim data, we have not performed interim analyses. We chose to investigate the internal carotid artery because it is a major vessel and therefore likely to be representative of the general vasculature. Postmenopausal hormone replacement therapy is thought to impart benefit to the cerebrovascular circulation, the internal carotid is readily accessible for ultrasound investigation, and it does not (unlike the uterine artery) supply oestrogen-dependent tissue that may alter downstream blood flow impedance. Arterial pulsatility index appears to rise following the menopause, possibly reflecting reduced compliance and increased peripheral resistance within aged vessels. Treatment with oestrogen therapy for weeks caused a significant drop in the carotid artery pulsatility index; this substantiates
4 HRT AND CAROTID ARTERY PULSATILITY INDEX 411 findings from previous uncontrolled studies, suggesting dilatation of cerebral arterioles and decreased resistance to blood flow, with a continued rise in the pulsatility index of women receiving placebo. This effect was observed despite a proportion of women within the study being elderly, agreeing with epidemiological observations of cardiovascular benefit in an aged populati~n~~. Whether a threshold serum oestrogen level is necessary to observe these benefits is unclear from this small study. All the women were postmenopausal, although one woman had an initial serum oestradiol of 147 pmol/l (above the postmenopausal threshold of 100 pmol/l); she was 73 years of age, had a body mass index of 37 and was randomised to receive placebo. All women demonstrated a rise in serum oestradiol levels after treatment with oestradiol valerate (2 mg daily), but the levels were still in many cases below those seen in premenopausal women. Greater changes in pulsatility index may be observed with higher serum concentrations, although in this study a correlation between serum oestradiol and changing pulsatility index was not seen. Furthermore, the response will be affected by carotid oestradiol receptor concentration and steroid binding, neither of which have been measured. Carotid blood flow can be affected by extraneous variables such as physical activity, temperature, food intake, light and noisei4. Habituation may occur with repeated analyses, as the woman becomes familiar with the hospital environment and the nature of the investigation. Uncontrolled studies may therefore be subject to bias. Rigorous methodology such as white noise, has been employed in previous worki4 in an effort to overcome some of the difficulties. The risk of bias may be decreased in any double-blind placebo controlled randomised trail; but in an attempt to eliminate bias we ensured that consecutive measurements were conducted at the same time of day in a recumbent resting position, in the same sound-proof room, kept at a constant temperature and lighting intensity. Some women experienced break-through bleeding and were given cyclical progestogen therapy in addition to oestrogen. Much of the data showing cardiovascular benefit from HRT is from earlier studies where oestrogen was given in isolation. Concern has been expressed that adding a progestogen may be detrimental, although recent epidemiological data suggests that this is not the case The limited data from the women in our study who received progesterone in addition to oestrogen suggest that the observed benefit on pulsatility index is maintained; similar benefits have been reported in an uncontrolled study using continuous combined oestrogen-progestogen therapyz9. Therefore, although the findings of this study are only directly applicable to women who have had a hysterectomy who would be on unopposed therapy, it supports the proposition that combined hormone replacement therapy may confer similar benefits. CONCLUSION This study confirms previous uncontrolled reports that carotid arterial pulsatility index is significantly decreased by administering systemic oestrogen to postmenopausal women. By undertaking a double blind placebo controlled trial we have shown these observations are not due to either habituation or investigator bias. We conclude that oestrogen decreases postmenopausal peripheral vascular resistance in postmenopausal women, demonstrating a further important mechanism whereby HRT may impart cardiovascular protection. References 1 Grimes DA. Prevention of cardiovascular disease in women: role of the obstetrician-gynecologist. Anr J Obster Gynecol 1988; 158: Stampfer MJ, Colditz GA, Willett WC et al. 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