Department of Obstetrics and Gynaecology, King's College Hospital, Denmark Hill, London SE5 8RX, UK
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Abstract |
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Key words: blood flow/circadian rhythm/Doppler ultrasound/uterine artery
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Introduction |
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A number of observational studies have shown cardioprotective effects of exogenous oestrogens in post-menopausal women (Bush et al., 1987; Paganini-Hill et al., 1988
; Stampfer et al., 1991; Walsh et al., 1991
). The reduction in cardiovascular risk can only partly be explained by changes in blood lipids and lipoproteins. Doppler studies have shown that vasodilatation in the uterine artery occurs soon after starting treatment with parenteral oestrogens (Bourne et al., 1990
; de Ziegler et al., 1991
; Cacciatore et al., 1998
). Other studies have shown that changes in serum lipid concentrations following oestrogen therapy take ~3 weeks (Bush et al., 1987
; Whitcroft et al., 1994
; Kim et al., 1996
) and therefore it is unlikely that the rapid response of vasodilatation of the uterine artery following administration of oestrogens is mediated by changes in blood lipid concentrations. However, it is not known to what extent uterine blood flow in post-menopausal women may be influenced by mechanisms other than hormone replacement therapy (HRT). In particular the presence of circadian rhythm may affect Doppler measurements and lead to erroneous conclusions about the effects of different ovarian steroids on uterine and systemic circulations.
In this study we investigated whether circadian changes in uterine artery blood flow are also present in post-menopausal women during the oestrogen-only phase of sequential HRT.
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Materials and methods |
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All women were prescribed sequential HRT as continuous transdermal oestradiol 50 µg/24 h (Evorel; Janssen-Cilag, Saunderton, UK) and cyclical oral norethisterone 1 mg/24 h or dydrogesterone 10 mg/24 h for 12 days each month. Patches were changed twice weekly after 3.5 days in accordance with the manufacturer's instructions. Examinations were performed during days 2 and 4 of the second week of the oestrogen-only phase of the cycle to avoid the effects of progestogen on uterine blood flow (Marsh et al., 1994). All scans were performed 24 h after the patches were changed. Women were first seen between 0800 and 0830 h and then again between 1800 and 1830 h on the same day. Resting blood pressure and heart rate were taken once at each visit after a 30 min rest. A peripheral venous blood sample was then obtained and serum stored at 70°C for measurement of oestradiol concentrations. The hormone concentrations were measured using a commercially available direct radioimmunoassay kit (Technicon Immuno 1; Bayer Diagnostics, Newbury, Berkshire, UK). The within-batch coefficients of variation, calculated from previous assays performed in the Department of Clinical Biochemistry at King's College Hospital, was 1.8% for oestradiol.
All ultrasound examinations were performed by a single operator (D.J.) using a 5 MHz transvaginal probe with colour and pulsed Doppler facilities (Aloka SSD-2000; Aloka Ltd, Tokyo, Japan). Colour Doppler signal was used to identify the main uterine artery lateral to the cervix at the level of the internal os. A pulsed Doppler range gate was then placed across the vessel, aiming for an angle close to 0° between the Doppler beam and the vessel. The pulse repetition frequency ranged from 1 to 12 kHz and the filter used was 50 Hz. Flow velocity waveforms were obtained from both uterine arteries. The pulsatility index (PI), the resistance index (RI), the peak systolic velocity (PSV) and the time-averaged maximum velocity (TAMXV) were calculated electronically from regular curves fitted to good-quality, high-amplitude waveforms. PI was used as a measure of impedance to blood flow distal to the point of sampling and was calculated according to the formula:
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Results |
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Discussion |
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Circadian rhythms are known to exist and play an important role in the regulation of physiological functions in the human body. For example, they are known to influence the secretion of many hormones, such as prolactin, adrenocorticotrophin hormone and cortisol (Weitzman, 1976). The influence of circadian rhythms on vascular reactivity and tone has been reported in previous studies (Millar-Craig et al., 1978
; Panza et al., 1991
; Feng and Tofler, 1995
). In these studies increased vasoconstrictor activity, higher blood pressure and vascular tone have been reported during the morning periods as compared to the evening times. A circadian variation in alpha-adrenergic activity has also been demonstrated and it has been postulated that increased vasoconstriction and vascular tone is mediated by high basal alpha-adrenoceptor activity in the morning (Panza et al., 1991
). This group demonstrated that basal forearm vascular resistance was significantly higher and the blood flow significantly lower in the morning than in the afternoon and evening. These findings contrast with the results of our study, where uterine artery blood flow impedance is higher in the evening compared with morning. Circadian variations have also been described for platelet aggregation (Petralito et al., 1982
), blood viscosity (Ehrly and Jung, 1973
), activated partial thromboplastin and thrombin time (Decousus et al., 1985
; Tofler et al., 1987
). These studies show increased tendency to thrombosis in the morning as compared with the afternoon. Melatonin has also been shown to be secreted in a circadian pattern, with nearly all being secreted at night and secretion being absent during the day (Cagnacci et al., 1998
). The effects of melatonin on the circulation are mainly those of vasodilatation, which may partly explain the variations observed in uterine artery blood flow.
The majority of Doppler studies in post-menopausal women have shown a significant decrease in uterine artery impedance to flow following administration of exogenous oestrogens (Hillard et al., 1992; Marsh et al., 1994
; Dören et al., 1997
; Järvelä et al., 1997
; Cacciatore et al., 1998
). This effect appears to be counteracted to an extent by the addition of progestogens. A decrease in central retinal artery resistance was reported (Belfort et al., 1995
) and consequently the cerebral microcirculation following oestrogen replacement therapy. However, not all of these studies allowed for diurnal variations in blood flow. For example a recent report demonstrated a rise in the PI value in women receiving exogenous oestradiol treatment after the administration of progestogens (Hillard et al., 1992
). The average increase in the impedance to flow was 13% which is much less than circadian fluctuations observed in our study.
In another study (Järvelä et al., 1997), 13 post-menopausal women were treated with unopposed transdermal oestradiol patches alone for 1 month. This was then followed by insertion of the levonorgestrel-releasing intrauterine device. This group demonstrated an initial decrease in mean uterine artery PI after 1 month of transdermal oestradiol treatment; this was followed by an 11% increase in the mean uterine artery PI 1 month following the insertion of the progestogen-releasing intrauterine system. However, from the data it is clear that this result was due to a significant increase in resistance to flow in a minority of patients. It is, therefore, possible that underlying diurnal blood flow changes could have significantly influenced the final result. In contrast, in another randomized trial (Cacciatore et al., 1998
) of women on oral and transdermal HRT, the examination time was standardized between 0800 and 1000 h. No opposing effects of progestogens on oestrogen-induced decrease in uterine artery PI were demonstrated in either treatment group. Similar results have been reported by others (Lau et al., 1998
; Exacoustos et al., 1999
). It remains to be seen to what extent these contradictory results can be explained by the effects of physiological blood flow variations. In addition, a different study design, for example randomized with a control group, may give more information regarding the magnitude of the effect.
Blood flow measurements in the uterine and other pelvic arteries play an increasingly important role in diagnosing gynaecological pathology (Järvelä et al., 1998) and in defining the best time for embryo transfer in IVF (Battaglia et al., 1998
), amongst other applications. The accuracy of blood flow measurements may be affected by factors such as the quality of the ultrasound equipment, accessibility of the vessel of interest and the experience of the operator. In addition it is important to be aware of the influence of circadian rhythms on uterine blood flow and it is imperative that all future studies control for this to enable meaningful comparisons of the results.
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Notes |
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References |
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Submitted on May 12, 1999; accepted on August 4, 1999.